Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[C:22]([O:29]C)[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:20]2[NH:21][C:22](=[O:29])[C:23]([N:26]([CH3:27])[CH3:28])=[CH:24][CH:25]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N(C)C
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(dimethylamino)-6-methoxypyridin-2-yl]ethenyl}pyrrolidin-2-one (41 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) and crystallized from chloroform-ethyl acetate to give the title compound as a light yellow powder (11 mg, 26% (two steps)).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:39][C@@H:40]([CH3:41])[C:42]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:43]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)[C@H](C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 61 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 60 mg Boc-L-Alanine via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 52.7 mg of 354 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH3:28][O:29][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: COc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(OC)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Chloro-6-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example ε(100 mg, 0.25 mMol) was added to freshly prepared sodium methoxide (0.27 mMol) in methanol and stirred at room temperature for 22 hours and then at 75° C. for 4 hours. The reaction solution was concentrated and the product was purified by silica gel chromatography to give a white solid. Anal. Calc'd. for C21H18N2O4S (394.45): C, 63.95; H, 4.60; N, 7.10. Found: C, 63.80; H, 4.71; N, 6.94.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:16])[CH:12]=[CH2:13]>CN(C)C=O>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:19]1)(=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCc1cccnc1
Temperature: 0 °C

Procedure:
To a solution of potassium t-butoxide (1.50 g) in N,N-dimethylformamide (20 ml) was added dropwise thioacetic acid (0.96 ml) with stirring at -10°~-5° C. The mixture was stirred at the same temperature for 10 minutes. A solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.39 g) in N,N-dimethylformamide (20 ml) was added to the mixture obtained above with stirring at the same temperature. The mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (120 ml) and extracted three times with ethyl acetate (80 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.12 g).
Reaction SMILES: Br[C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[OH:15])=[O:4].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:2]1([CH3:17])[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=2[O:15]1
Reactant: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide was mixed with K2CO3 in 20 mL of DMF and stirred overnight at 50° C. The reaction mixture was poured into ice water. The precipitate was collected by filtration and washed with H2O. The crude compound was recrystallized from EtOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[C:60]([O:66][CH3:67])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:25]([CH:28](/[CH:46]=[CH:47]/[C:48]1[C:53]([O:54][CH3:55])=[CH:52][C:51]([O:56][CH3:57])=[CH:50][C:49]=1[O:58][CH3:59])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:38](=[O:45])[CH:39]([O:41]C(=O)C)[CH3:40])[CH:30]=1)(=[O:27])=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:24])[CH:18]([O:20]C(=O)C)[CH3:19])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:55][O:54][C:53]1[CH:52]=[C:51]([O:56][CH3:57])[CH:50]=[C:49]([O:58][CH3:59])[C:48]=1/[CH:47]=[CH:46]/[CH:28]([S:25]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:3]([O:2][CH3:1])=[CH:63][C:62]([O:64][CH3:65])=[CH:61][C:60]=1[O:66][CH3:67])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:17](=[O:24])[CH:18]([CH3:19])[OH:20])[CH:9]=1)(=[O:26])=[O:27])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:38](=[O:45])[CH:39]([OH:41])[CH3:40])[CH:30]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)O)c2)c(OC)c1

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-3-(2-acetoxypropionamido)-4-methoxybenzylsulfone (10 mmol) was hydrolyzed with potassium carbonate (70 mmol) in 1:1 ethanol/water (25 mL) to give (E)-2,4,6-trimethoxystyryl-3-(2-hydroxy-2-methylacetamido)-4-methoxy benzylsulfone. (m.p. 174-1 76° C.)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][CH:5]=1.N([O-])=O.[Na+].[CH:15](=[O:21])[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:19]2[O:20][C:16]([CH:15]=[O:21])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccco1
Reactant: COc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C=O)o2)cc1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A 5l. three-necked flask equipped with stirrer, thermometer and dropping funnel was charged with water (150ml), concentrated HCl (400 ml) was introduced, followed by p-anisidine (185 g, 1.5 moles). A solution of sodium nitrite (108 g, 1.56 moles) in water (300 ml) was introduced dropwise maintaining -10° to -5°C. Furfural (184 g, 1.92 moles) was introduced followed by a solution of CuCl2.2H2O (46 g) in water (300 ml). The reaction mixture was heated to 53° with hot water maintaining 53°-68° for 2.5 hours. After cooling to room temperature overnight, the reaction mixture was extracted with ether (1800 ml). The dried (MgSO4) extract was evaporated in a rotary evaporator, and the residue was distilled under reduced pressure to give 70 g of black semi-solid product (b.p. 160°-190° at 2-5 mm).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][C:9]([CH:11]([O:14][NH2:15])[CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][C:23]1[S:24][CH:25]=[C:26]([C:28](=O)[C:29]([OH:31])=[O:30])[N:27]=1>CN(C)C=O.ClCCl>[NH2:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:15]/[O:14][CH:11]([C:9]([O:8][CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:12][CH3:13])/[C:29]([OH:31])=[O:30])[N:27]=1
Reactant: CCC(ON)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
30 g of O-(1-diphenylmethoxycarbonylpropyl)hydroxylamine and 16.2 g of (2-amino-4-thiazolyl)glyoxylic acid are stirred for 1 hour at room temperature in 60 ml of dimethylformamide. The reaction mixture is diluted with dichloromethane, and washed with 2N hydrochloric acid and several times with water. After evaporating the dichloromethane phase, 41 g of the title compound remain as a solid residue.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].ClCCl>CO>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)OC
Reactant: CCCCNCCCC
Solvent: CO
Solvent: ClCCl
Product: CCCCN(CCCC)CCC(=O)OC
Temperature: 50 °C
Yield: 94.5 %

Procedure:
A! A solution of dibutylamine (1 l, 5.88 moles) in methanol (2.35 l), kept under stirring at 50° C., was slowly added dropwise with methyl acrilate (1.051 l, 11.76 moles). The mixture was then brought to room temperature and kept under stirring for 1 hour, thereafter 1.174 l of dichloromethane were added and the product extracted with 4.7 l of 3N HCl. The organic phase was washed with water (3×2.35 l). The aqueous phase was brought to pH-9 with 5N sodium hydrate and extracted with dichloromethane (2×2.35 l). The organic phase was washed with 2.35 l of distilled water, then anhydrified over sodium sulfate and evaporated under vacuum thus obtaining 1197 g of methyl N,N-dibutyl-3-amino-propionate (yield: 94.5%) as a pale yellow oil which was used as such in the next step.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:47](N)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=1>CN(C)C=O>[ClH:1].[ClH:1].[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][C:9]5[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][C:47](=[O:54])[C:48]6[CH:53]=[CH:52][CH:51]=[N:50][CH:49]=6)=[CH:38][CH:37]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: NC(=O)c1cccnc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)c4cccnc4)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
A mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (15 ml) was stirred at room temperature for 30 minutes. To the mixture was added nicotinamide hydrochloride (0.1 g) and this mixture was irradiated with ultrasound for 30 minutes, stirred at room temperature for 6 hours and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between a mixture of ethyl acetate:tetrahydrofuran (1:1) and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by liquid chromatography (LiChroprepDIOL (MERCK)) using ethyl acetate:tetrahydrofuran=3:1 as the eluant. To a solution of the glassy product in tetrahydrofuran (5 ml) was added 4N hydrogen chloride in 1,4-dioxane (5 ml) and the mixture was irradiated with ultrasound for 30 minutes. The precipitate was isolated by filtration to afford the title compound (0.15 g, pale yellow powder, mp 176-180° C. (dec)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[OH:38][CH2:37][C:36]([NH:35][S:32]([C:28]1[CH:27]=[C:26]([NH:25][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])([CH3:40])[CH3:39]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 599.8 [(M−H−]; mp 269° C.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](Cl)=[O:17])[CH3:11].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](=[O:17])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1)[CH3:11]
Reactant: C[Si](C)(C)c1nccs1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-trimethylsilanyl-thiazole (2.6 g, 16.53 mmol) in DCM (30 mL) is added a solution of 3-chlorocarbonyl-propionic acid ethyl ester (5.4 g, 32.81 mmol) in DCM (10 mL). The mixture is stirred overnight at room temperature. To the mixture is added 5% NaHCO3 (30 mL) and mixture is stirred at room temperature for 20 minutes. The organic layer is separated and the aqueous lay is extracted with DCM (2×50 mL). The combined organic layers are dried and the solvent removed. The residue is separated by column (methylene chloride) to give 4-oxo-4-thiazol-2-yl-butyric acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=O)[C:4]=2[CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:17][NH2:18])[C:4]=2[CH:3]=1
Reactant: NN
Reactant: O=C1c2ccccc2-c2ccc(F)cc21
Solvent: O
Solvent: CCO
Product: NN=C1c2ccccc2-c2ccc(F)cc21
Yield: 60 %

Procedure:
A mixture of commercially available (Aldrich Chemical, Inc.) 2-fluoro-9-fluorenone (11) (10 g, 50.5 mmoL) and hydrazine monohydrate (10 mL , 200 mmoL, 4 eq) in ethanol (250 mL ) was refluxed for 1.5 h. The solution was then reduced in volume (to about a 100 mL) and chilled. The solid that separated was collected by filtration, washing with cold ethanol to provide 6.5 g (60%) of product (12): mp 161°-165° C.; IR (KBr) 3390, 3310, 3200, 1450 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.85 (bd, 1H, J=7.3Hz), 7.69 (bd, 1H, J=7.1Hz), 7.57 (dd, 1H, J=4.8, 8.1Hz), 7.36 (m, 3H), 7.02 (ddd, 1H, J=2.5, 8.3, 9.2Hz), 6.48 (bs, 2H); MS m/z 212 (M+), 183 (base peak).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)c4ccccc4)cc23)CC1

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 10.1 mg (0.059 mMol) N-methyl-N-phenyl carbamoyl chloride, 17.4 (86%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[H-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH2:10][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)(C)c1ccc(Cl)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 3-(4-chlorophenyl)-3-methyl-2-butanone (197 mg, 1 mmol) in diethyl carbonate (1.32 g, 11 mmol) was added at 20° C. under an atmosphere of nitrogen portion wise a dispersion of 55% sodium hydride in mineral oil (91 mg, 2.1 mmol). The reaction turned yellow and was heated to 50° C. After the gas evolution stopped the reaction was stirred at 85° C. for 30 min. After cooling to 20° C. the reaction was poured onto ice-water (2 mL) and then acetic acid (0.14 mL) was added. The reaction was extracted twice with diethyl ether. The combined organic layers were washed with water and with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using heptene/ethyl acetate (9:1 v/v) as eluent to yield the title compound as a pale-yellow oil (79 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:5]([C:7]([N:9]2[CH2:16][C@H:15]3[C@H:11]([CH2:12][C:13]([F:18])([F:17])[CH2:14]3)[C@H:10]2[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])[N:6]=1.O.NN>CCO>[NH2:20][CH2:19][C@H:10]1[N:9]([C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[O:8])[CH2:16][C@H:15]2[C@@H:11]1[CH2:12][C:13]([F:18])([F:17])[CH2:14]2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of (1S,2S,5R)-2-[3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-7,7-difluoro-3-azabicyclo[3.3.0]oct-2-ylmethyl)-isoindole-1,3-dione (130 mg), hydrazine monohydrate (0.078 mL) in EtOH (10 mL) was stirred at reflux for 1 h 45. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM, washed twice with water, brine, dried (MgSO4), filtered and concentrated to yield the title compound (90 mg, 92%) as a colorless oil which was used for the next step without further purification. LC-MS: tR=0.79 min; [M+H]+=392
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:15][CH2:14][C@H:13]([NH:16][O:17][CH2:18][CH:19]=[CH2:20])[CH:12]=[C:11]1[CH3:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:31](OC(Cl)(Cl)Cl)(OC(Cl)(Cl)Cl)=[O:32]>C(#N)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH3:21])=[CH:12][C@@H:13]2[CH2:14][N:15]1[C:31](=[O:32])[N:16]2[O:17][CH2:18][CH:19]=[CH2:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCON[C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCON1C(=O)N2C[C@H]1C=C(C)[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: -15 °C
Reaction time: 3 h
Yield: 117.9 %

Procedure:
Into a 2000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (3R,6S)-6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-N-(prop-2-en-1-yloxy)-1,2,3,6-tetrahydropyridin-3-amine (Intermediate 147, 8.4 g, 26.88 mmol, 1.00 equiv) in acetonitrile (1600 mL), N,N-Diisopropylethylamine (14.2 g, 109.87 mmol, 4.00 equiv). This was followed by the addition of a solution of ditrichloromethyl carbonate (2.9 g, 9.77 mmol, 0.40 equiv) in acetonitrile (100 mL) dropwise with stirring at −15° C. in 3 hr. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of ethyl acetate. The resulting mixture was washed with 2×400 mL of NH4Cl (aq.) and 2×400 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 3.9 g (43%) of the title compound as yellow oil.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]2[CH2:17][CH2:16][C:13]3([CH2:15][CH2:14]3)[CH2:12][C:11]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C@@H:2]3[CH2:6][CH2:5][C@H:4]([C:7]([NH:9][C:10]4[CH2:17][CH2:16][C:13]5([CH2:15][CH2:14]5)[CH2:12][C:11]=4[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH2:3]3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)C1=C(NC(=O)[C@H]2CCC(=O)C2)CCC2(CC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NC(=O)[C@H]2CC[C@@H](N3CCN(c4ccc(F)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
To a solution of (S)-ethyl 6-(3-oxocyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylate (0.7 g, 2.23 mmol) in 1,2-dichloroethane (10 ml) were added 1-(4-fluorophenyl)piperazine (0.43 g, 2.40 mmol), glacial acetic acid (0.14 g, 2.40 mmol) and sodium triacetoxy borohydride (0.7 g, 3.44 mmol). The mixture was stirred at RT for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain a diastereomeric mixture (7:3) of title compound (0.9 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:16]1[NH:17][CH:18]=CN=1)=O.CNC>CN(C=O)C>[CH3:16][N:17]([CH3:18])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CNC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
3-Methyl-4-nitrobenzoic acid (3.0 g, 16.56 mmol) in DMF (30 mL) was stirred with carbonyl diimidazole (3.22 g, 1.2 Eq.) for 90 mins. The reaction mixture was cooled in an icebath, and dimethylamine (2 M in THF, 25 mL, 3 Eq.) was added. The mixture was then allowed to warm to room temperature and stirred for 2 hours. The mixture was poured onto ice water (200 ml) and extracted with EtOAc (×6). The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated. Tritration with ether followed by filtration gave N,N,3-trimethyl-4-nitrobenzamide (2.6 g, colourless solid); MS (ES+) 209.