Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CO.C[O-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>Cl>[CH:16]1([CH2:15][O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrCC1CCCCC1
Reactant: Oc1ccccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ccccc1OCC1CCCCC1
Temperature: 25 °C
Yield: 31 %

Procedure:
An oven-dried 10 mL round-bottom flask equipped with condenser was charged with catechol (198 mg, 1.80 mmol), MeOH (2 mL), and NaOMe (102 mg, 1.89 mmol) and purged with nitrogen. (Bromomethyl)cyclohexane (319 mg, 1.80 mmol) was added and the reaction was heated to reflux for 48 hours. After cooling to room temperature the reaction was diluted with 50 mL 1M HCl and extracted with DCM (3×25 mL). The combined organic layers were washed with saturated NaCl (1×25 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (3:1 hexane:Ethyl acetate) afforded an off-white solid weighing 114 mg (31% yield). Off-white solid; 1H NMR (CDCl3): δ 1.03-1.11 (m, 2H), 1.18-1.35 (m, 3H), 1.71-1.88 (m, 6H), 3.84 (d, J=6.35 Hz, 2H), 5.64 (s, 1H), 6.80-6.88 (m, 3H), 6.92-6.94 (m, 1H); 13C NMR (CDCl3): δ 25.88, 26.59, 30.05, 37.80, 74.39, 111.77, 114.55, 120.20, 121.14, 121.38, 145.99; HRMS (FAB): 206.13068 calcd for C13H18O2 [M]+. found 206.12952 (−5.7 ppm, −1.2 mmu).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:18][CH3:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][NH:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)Cc1ccccc1OCc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1ccccc1OCc1ccccc1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
At 0° C., a solution of 2-(2-benzyloxyphenyl)-N-methylacetamide (9.39 g, 36.8 mmol) in tetrahydroufran (150 ml) was added dropwise to a suspension of sodium borohydride (1.67 g, 44.12 mmol) in tetrahydrofuran (100 ml). After the addition was finished, a solution of iodine (4.67 g, 18.39 mmol) in tetrahydrofuran (200 ml) was added dropwise. The solution was warmed to reflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in an aqueous 20% sodium hydroxide solution (200 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×75 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using dichloromethane/methanol/25% aqueous ammonia as eluent (100:10:1), to give 4.38 g of N-(2-(2-benzyloxyphenyl)ethyl)-N-methylamine.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:23]([NH:25]N)=[O:24])[CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.N([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+].[C:38]([O:41][CH2:42]C)(=[O:40])[CH3:39]>>[CH3:42][O:41][C:38](=[O:40])[C@H:39]([CH2:4][CH:5]([CH3:10])[CH3:6])[NH:25][C:23](=[O:24])[C@H:16]([CH2:17][C:18]1[N:22]=[CH:21][NH:20][CH:19]=1)[NH:15][C:13](=[O:14])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCOC(C)=O
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
21 g of carbobenzoxyglycyl-L-histidine hydrazide is dissolved in 185 ml of 1 N.HCl and to this solution is added 245 ml of ethyl acetate and 4.3 g of NaNO2 at 0° C. with stirring, and after five minutes, 73 ml of a 50% aqueous solution of K2CO3 is added and then this solution is extracted with ethyl acetate. After the extract is dehydrated over anhydrous sodium sulfate, a solution (cooled to 0° C.) of L-leucine methyl ester in ethyl ether (9 g/208 ml) is added to the extract, and this mixture is left to stand overnight at -5° C. The crystals thus produced are filtered off, and washed with ethyl ether to obtain carbobenzoxyglycyl-L-histidyl-L-leucine methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([F:13])([F:12])[F:11].CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:9][C:4]1[C:3]([C:10]([F:13])([F:12])[F:11])=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1cc(F)c(C(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 85 °C
Yield: 117.7 %

Procedure:
A mixture of l-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (25, 0.200 g, 0.76 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.237 g, 0.76 mmol), Pd(dppf) (0.056 g, 0.077 mmol), and 2 N Na2CO3 (2 mL, 4 mmol) in DME (3 mL) was heated to 85° C. for 5 h. The mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3×75 mL). The combined organics were dried over Na2SO4, concentrated under reduced pressure, and the resulting residue was chromatographed over silica gel (24 g Redisep column, 0-25% EtOAc in hexanes) to afford tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (26) as a light yellow oil (0.325 g, 90%). 1H NMR (300 MHz, CDCl3) δ 6.92-6.80 (m, 1H), 6.78-6.68 (m, 1H), 5.58 (s, 1H), 4.06-3.94 (m, 2H), 3.69-3.53 (m, 2H), 2.36-1.24 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][C:12]([CH2:14][CH3:15])=[CH:11][C@H:10]1[C:16]([OH:18])=[O:17])=[O:8])(=O)C.N>>[CH2:14]([C:12]1[CH2:13][N:9]([C:7](=[O:8])[CH2:6][CH2:5][SH:4])[C@H:10]([C:16]([OH:18])=[O:17])[CH:11]=1)[CH3:15]
Reactant: CCC1=C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: CCC1=C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 4 to yield (2S)-2,5-dihydro-4-ethyl-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].CCN(C(C)C)C(C)C.[C:33]1([C@H:39]([NH2:41])[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN1C(=O)CCC1.O.C(Cl)Cl>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:41][C@@H:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:40])=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(N[C@H](C)c3ccccc3)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Temperature: 120 °C
Yield: 84 %

Procedure:
4-Chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 9) (3.33 g, 10.04 mmol) was dissolved in NMP (10 ml) and DIPEA (1.8 ml, 10 mmol) and [(1R)-1-phenylethyl]amine (1.58 g, 13.05 mmol) were added, then the solution was heated at 120° C. for 18 h, then cooled to room temperature, diluted with water (100 ml) and extracted with EtOAc (2×100 ml). The organic layer was washed with water (2×100 ml), dried with sodium sulphate and evaporated in vacuo to give a brown gum. This was dissolved in DCM 20 ml) and loaded onto a 100 g silica cartridge, then eluted with MeOH/DCM (0-10%) and product-containing fractions evaporated in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4-{[(1R)-1-phenylethyl]amino}-3-quinolinecarboxamide (3.5 g, 8.40 mmol, 84% yield) as a beige solid. LCMS (formate) Rt 0.84 min, MH+ 417
Reaction SMILES: [CH2:1]1[CH2:8][O:7][C:3]([CH3:6])([CH2:4][OH:5])[O:2]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>[H-].[Na+].C1C=CC=CC=1>[C:12]([O:5][CH2:4][C:3]1([O:7][CH2:8][CH2:1][O:2]1)[CH3:6])(=[O:13])[CH2:11][C:10]([CH3:9])=[O:14]
Reactant: CC1(CO)OCCO1
Reactant: C=C1CC(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)CC(=O)OCC1(C)OCCO1
Yield: 62.8 %

Procedure:
100 mg of 50% sodium hydride was added to a mixture of 20 g of 2,2-ethylenedioxypropanol and 100 ml of benzene, and 20 g of diketene was added dropwise to the mixture while refluxing the mixture. After refluxing the mixture for 2 hours, the solvent was distilled off and the resulting residue was distilled under reduced pressure to obtain 21.5 g (70% yield) of 2,2-ethylenedioxypropyl acetoacetate as a colorless oil having a boiling point of 90° C. (6 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]([NH:26][NH2:27])=[O:25])[CH:21]=[C:20]([Cl:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].CN([CH:32]=[O:33])C>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[O:25][C:32](=[O:33])[NH:27][N:26]=3)[CH:21]=[C:20]([Cl:28])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)cc(Cl)n3)CC2)c(Cl)c1Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(-c4n[nH]c(=O)o4)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N,N′-Carbonyldimidazole (0.021 g, 0.13 mmol) was added to a stirred solution of 3,4-dichloro-N-{1-[6-chloro-4-(hydrazinocarbonyl)pyridin-2-yl]piperidin-4-yl}-5-methyl-1H-pyrrole-2-carboxamide (Example 309) (30 mg, 0.06 mmol) in DMF (2 ml). The mixture was stirred at room temperature for 6 h. The mixture was filtered and purified by semi-preparative HPLC eluting with CH3CN/H2O (0.1% TFA) mixtures to give the title compound (15 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.CCOCC.[N+](=[CH:66][CH2:67][CH3:68])=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:66][CH2:67][CH3:68])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCC=[N+]=[N-]
Agent: FB(F)F
Solvent: CCOCC
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in ether (6 ml) is added borontrifluoride etherate (10 μl) followed by freshly prepared 1-diazopropane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica gives the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:33]2[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(C#N)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-cyanophenylboronic acid. The title compound was obtained in 31% yield as yellow foam. MS (m/e): 473.2 (MH+, 100%).
Reaction SMILES: C1(S([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:47])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=O)=O)CC1.[C:54](Cl)(=[O:56])[CH3:55]>>[C:54]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:9][CH2:8]1)(=[O:56])[CH3:55]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(=O)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(C)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using acetyl chloride as the reagent in Step 1. The product was isolated as a white solid (5.4 mg, 35%). LCMS: m/e 684.67 (M+H)+, 2.27 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.82 (s, 1H), 4.72 (s, 1H), 4.09-3.89 (m, 1H), 3.85 (br. s., 3H), 3.68 (br. s., 4H), 3.53-3.14 (m, 4H), 2.92-2.66 (m, 1H), 2.28-1.01 (m, 22H), 2.17 (s, 3H), 1.73 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN1CCN(C(=O)NCc2nccnc2Cl)CC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2ncc3c(Cl)nccn23)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To N-((3-chloropyrazin-2-yl)methyl)-4-methylpiperazine-1-carboxamide (485 mg) in acetonitrile (3 mL) under a N2 flow was added phosphorus oxychloride (878 μl) and heated at 60° C. (bath temperature) for five hours and at 80° C. for one hour. Then the reaction mixture was concentrated in vacuo. Toluene was added and the mixture was concentrated in vacuo. Residue was taken up with acetonitrile, 7N ammonia in methanol was added with cooling and the suspension was stirred for 16 hours, then filtered and the filtrate concentrated in vacuo. Dichloromethane was added to the residue, again filtered and the filtrate concentrated in vacuo to give 8-chloro-3-(4-methylpiperazin-1-yl)imidazo[1,5-a]pyrazine (400 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][NH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][O:25][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NOC1CCCCO1
Product: O=C(NOC1CCCCO1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(tetrahydro-2H-pyran-2-yloxy)isonicotin-amide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.4 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.52 mmol of O-(tetrahydro-pyran-2-yl)-hydroxylamine. LC/MS [9.07 min; 458 (M+1)]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc(C=O)o2)cc1
Reactant: CC(C)(C)NO
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)o2)cc1
Yield: 86.2 %

Procedure:
2-(4-Methoxyphenylthio)-5-furaldehyde (24.50 g) was mixed with N-tert-butylhydroxylamine (15.0 g, 168.16 mmol), molecular sieves (100 g) and silica gel (20 g) in CHCl3 (500 mL). The mixture was refluxed overnight under argon gas, and then filtered and concentrated on a rotary evaporator. The residue was recrystallized from hexanes (435 mL) to afford the title compound as yellowish crystals (27.52 g, yield 78.8%), m.p. 91.7° C. (Rf =0.15 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[F:27][C:28]([F:38])=[CH:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:34]([C:33]1[CH:32]=[CH:31][C:30]([CH:29]=[C:28]([F:27])[F:38])=[CH:37][CH:36]=1)[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1ccc(C=C(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(C=C(F)F)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.42 h
Yield: 81 %

Procedure:
In a nitrogen stream, a solution of 2-benzyloxybromobenzene (1.63 g, 6.18 mmol) in THF (4 mL) was cooled to −78° C., and an n-butyllithium hexane solution (2.44 M, 2.66 mL) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 25 minutes, and then a solution of 4-(2,2-difluorovinyl)benzaldehyde previously prepared in THF (1 mL) was added dropwise thereto. The reaction mixture was stirred at the same temperature for 1.25 hours, and then a saturated ammonium chloride aqueous solution and water was added thereto. The resulting mixture was extracted with ether and the organic layer was washed with a saturated ammonium chloride aqueous solution and dried over sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.17 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C1COCC1>[C:10]([Si:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(Cl)cc1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cc(Cl)ccc1N)(c1ccccc1)c1ccccc1
Yield: 31.1 %

Procedure:
2-Amino-5-chlorophenol (0.949 g, 6.61 mmol), tert-butylchlorodiphenylsilane (2.50 mL, 9.61 mmol), and imidazole (1.335 g, 19.6 mmol) were dissolved in THF (50 mL). Several days later, the reaction mixture was concentrated to give an oil which was purified by SiO2 column chromatography (eluent: 45% dichloromethane/55% hexanes). The product was dried ill vacuo to afford 2-(tert-butyl-diphenyl-silanyloxy)-4-chloro-phenylamine as a yellow oil (784.2 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ: 7.72-7.64 (m, 4H), 7.55-7.43 (m, 6H), 6.71 (d, J=8.45 Hz, 1H), 6.65 (dd, J=8.46, 2.27 Hz, 1H), 6.10 (d, J=2.26 Hz, 1H), 1.05 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH2:11])[CH2:5]2.[C@@:12]12([CH2:22][S:23]([OH:26])(=[O:25])=[O:24])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2.[C@@:12]12([CH2:22][S:23]([OH:26])(=[O:24])=[O:25])[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:13]2=[O:14].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH2:11])[CH2:5]2
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Product: N[C@H]1Cc2ccc(Br)cc2C1

Procedure:
The title compound was prepared using a similar method to that described in Prashad et al, Adv. Synth. Catal. 2001, 343, No. 5, pp 461-472: ie by resolution of the free base form of racemic 5-bromo-2-aminoindan using (1R)-(−)-10-camphorsulphonic acid to obtain (S)-5-bromo-2-aminoindan (1R)-(−)-10-camphorsulfonate salt.
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]1[C:9]#[N:10]
Reactant: N#Cc1ccc([N+](=O)[O-])[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 300 mg of 5-nitropyrrole-2carbonitrile (2.14 mol) in 15 mL of acetone, 360 mg of potassium carbonate (2.6 mmol) and 0.65 mL of iodomethane (1.6 mmol, 372 mg) are added. The mixture is then stirred at room temperature for 24 hours. The reaction mixture is poured into ice-water (100 mL) and the precipitate which forms is collected to yield (200 mg), 62% mp 86°-87° C. of 1-methyl-5-nitropyrrole-2-carbonitrile.