Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1C#C)(C)(C)C.[C:19]([O:23][C:24](=[O:41])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[C:35]#[C:36][Si](C)(C)C)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:41])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[C:35]#[CH:36])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#C[Si](C)(C)C
Agent: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Yield: 72 %

Procedure:
Following the general method as outlined in Intermediate 3, starting from tert-butyl{4-cyano-2-[(trimethylsilyl)ethynyl]phenoxy}acetate (Intermediate 45), the title compound was obtained as an oil in 72% yield.
Reaction SMILES: C([O:3][CH:4]([C@@H:6]1[C@@H:9]([S:10][CH3:11])[N:8]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:7]1=[O:20])[CH3:5])=O.C[O-].[Na+].C(O)(=O)C>CO>[OH:3][CH:4]([C@@H:6]1[C@@H:9]([S:10][CH3:11])[N:8]([C:12](=[C:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:7]1=[O:20])[CH3:5]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC=O)[C@H]1SC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (880 mg) in methanol (20 ml) was added a 4.9 M solution of sodium methoxide in methanol (0.60 ml) at 0° C. After 30 minutes, acetic acid (0.20 ml) was added and the mixture was evaporated. The residue was taken up into ethyl acetate (30 ml) and washed with a dilute aqueous sodium bicarbonate. Drying over magnesium sulfate and removal of the solvent left an oil, which was chromatographed on silica gel (25 g) eluting with 5-20% acetone in dichloromethane to give a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (742 mg).
Reaction SMILES: [CH2:1]([C:10]([OH:12])=O)[CH:2]([C:7]([OH:9])=O)[CH2:3][C:4]([OH:6])=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[NH2:20]>C1(C)C(C)=CC=CC=1>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[NH:20][C:4]([CH2:3][CH:2]([C:7]([NH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[CH3:13])=[O:9])[CH2:1][C:10]([NH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[CH3:13])=[O:12])=[O:6]
Reactant: O=C(O)CC(CC(=O)O)C(=O)O
Reactant: CC1CCCCC1N
Solvent: Cc1ccccc1C
Product: CC1CCCCC1NC(=O)CC(CC(=O)NC1CCCCC1C)C(=O)NC1CCCCC1C

Procedure:
Next, 3.52 g (20 mmol) of 1,2,3-propanetricarboxylic acid (made by Nacalai Tesque) and 13.6 g (120 mmol) of 2-methylcyclohexylamine were added to the xylene solution of a tricresol boric acid ester obtained above, and the contents were refluxed under heating and reacted for 3 hours. This gave a crude 1,2,3-propanetricarboxylic acid tris(2-methylcyclohexylamide) as a white solid.
Reaction SMILES: [O:1]1[CH2:4][C:3]2([CH2:9][CH:8]3[CH:6]([CH:7]3[C:10]([OH:12])=O)[CH2:5]2)[CH2:2]1.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH:7]1[CH:6]2[CH:8]1[CH2:9][C:3]1([CH2:5]2)[CH2:2][O:1][CH2:4]1)=[O:12]
Reactant: CNOC
Reactant: O=C(O)C1C2CC3(COC3)CC21
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CON(C)C(=O)C1C2CC3(COC3)CC21
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a solution of spiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxylic acid (0.70 g, 4.2 mmol) in dichloromethane (21 mL) was added carbonyl diimidazole (1.35 g, 8.33 mmol) at 15° C. After 30 min, N,O-dimethylhydroxylamine hydrochloride (487 mg, 4.99 mmol) was added in one portion. After 16 h, the reaction mixture was diluted with dichloromethane (50 mL), and the resulting mixture was washed with saturated aqueous sodium chloride solution (2×20 mL). The collected organic was concentrated, and the resulting residue was purified by flash column chromatography (30% ethyl acetate in petroleum ether) to afford product as a white solid (0.30 g, 34% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[O:4].I[C:16]1C=CC(N)=CC=1C>>[F:14][C:2]([F:1])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[C:8]([CH3:16])[CH:7]=1)=[O:4]
Reactant: Cc1cc(N)ccc1I
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Product: Cc1cc(NC(=O)C(F)(F)F)ccc1I

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 32, using 4-iodo-3-methylaniline as a substrate. ES/MS calcd. for C9H7F3INO 328.95. Found m/z=330 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[S:37])[NH:19]C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1CCCCC1.O>CN(C=O)C>[NH2:19][C:18]([NH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:12]1)=[S:37]
Reactant: O=C(NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving N-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide (553 mg, 1 mmol) in DMF (4 ml), piperidine (0.989 ml, 10 mmol) was added and the mixture was stirred at room temperature overnight. Upon completion of the reaction, water (20 ml) was added and extraction was performed with ethyl acetate (20 ml×3 times). The extracted organic layer was washed with water (100 ml×2 times) and then with saturated brine, dried over anhydrous sodium sulfate, and then filtered and concentrated. Purification was performed by silica gel column chromatography (ethyl acetate/methanol=1/0→4/1) to obtain amino[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]methane-1-thione. The compound was identified by LC-MS.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=O.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].C(OCC)C.O>C(OCC)C.CCCCCC>[F:8][C:9]([F:18])([F:19])[O:10][C:11]1[CH:12]=[C:13]([N:14]2[CH2:6][CH2:7][CH:2]([OH:1])[C:3]2=[O:5])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1OCCC1O
Reactant: Nc1cccc(OC(F)(F)F)c1
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C1C(O)CCN1c1cccc(OC(F)(F)F)c1
Temperature: 150 °C
Yield: 69.3 %

Procedure:
A mixture of alpha-hydroxy-gamma-butyrolactone (22.0 g) and 3-trifluoromethoxy aniline (19.0 g) was heated to 150° C. (bath temperature) for 48 hours. The mixture was allowed to cool and poured into a mixture of diethyl ether and water. After shaking, the ether layer was separated and the aqueous layer extracted with diethyl ether (x2). The combined ether extracts were washed with 2M hydrochloric acid, water and brine, then dried (MgSO4). The mixture was evaporated under reduced pressure to leave an oil, which on trituration with a mixture of diethyl ether/hexane gave the sub-title compound as an off-white solid (19.42 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][N:4]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:3][CH2:2][O:1][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:9][CH:10]=1)#[N:13]
Reactant: N#Cc1ccc(CCCNCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(CCCc1ccc(C#N)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a solution of 4-[3-(2-hydroxyethylamino)propyl]benzonitrile (4 g, 0.0196 mol; see step (v) above) in dry DCM (80 mL) were added, at 0-5° C., triethylamine (5.9 g, 0.0588 mol) and mesyl chloride (5.6 g, 0.049 mol). The resulting mixture was then stirred at room temperature for 30 min, after which the reaction was quenched by addition of water (50 mL). The resulting aqueous layer was extracted with DCM (2×50 mL) and the combined organic layers were washed with brine. Solvent was removed under reduced pressure and the crude product was recrystallised from methanol to yield 4.2 g (62%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[S:23][CH:24]=1)=[CH2:19]>CN1C(=O)CCC1.O>[S:23]1[CH:24]=[C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1csc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2csc3ccccc23)CCN(C)C1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (1 mL) were added powdered KOH (392 mg, 7.0 mmol) and 3-vinyl-benzo[b]thiophene (320 mg, 2.0 mmol). The reaction mixture was stirred at 90° C. for 5 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (5×25 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (3% MeOH-DCM) followed by reverse phase HPLC to yield 5-(2-benzo[b]thiophen-3-yl-ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.82 (d, 1H), 7.6 (d, 1H), 7.38 (m, 2H), 7.2 (m, 2H), 7.0 (d, 1H), 6.93 (s, 1H), 4.3 (t, 2H), 3.62 (s, 2H), 3.5 (s, 3H), 3.21 (t, 2H), 2.63 (t, 2H), 2.41 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([OH:27])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CCOC(=O)CCC(C)(C)c1ccc(Cl)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: -70 °C
Yield: 84.1 %

Procedure:
24.1 g (84.63 mmol) of ethyl-4-(4-chloro-3-methoxyphenyl)-4-methylpentanoate is dissolved in 296 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. to −65° C. Within 1¾ hours, 236.9 ml of a 0;5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture then is stirred for 75 more minutes at −70° C. 30.9 g (118.48 mmol) of Davis reagent, dissolved in 296 ml of tetrahydrofuran, is now added in drops within 60 minutes. After two hours of stirring at −70° C., 152 ml of saturated ammonium chloride solution is slowly added in drops, the cold bath is removed, and it is vigorously stirred for 30 minutes. After extraction with diethyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 21.4 g (84.2%) of the desired compound is isolated (easily contaminated).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11]>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CO)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)ccc1F
Yield: 90 %

Procedure:
(4-Fluoro-3-methoxyphenyl) methanol (5.00 g, 0.03 mol) and manganese dioxide (33.4 g, 0.38 mol) were stirred in dichloromethane (100 ml) under an atmosphere of nitrogen, at gentle reflux for 16 hours. The cooled reaction mixture was then filtered through arbacel and concentrated in vacuo to give the title compound as a white solid (4.18 g, 0.027 mol, 85%). 1H NMR (CDCl3, 400 MHz) δ: 3.96 (s, 3H), 7.23 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H) 9.91 (s, 1H). Mpt: 61-63° C. Analysis found C, 62.18; H, 4.54%. C8H7FO2 requires C, 62.34; H, 4.58%.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]2[NH:28][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:29][CH:30]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate and 4-nitrobenzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2,5-bis(4-nitrophenyl)imidazole-4-carboxylate, which is dissolved in ethyl alcohol. 1 M Sodium hydroxide solution is added and the mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2,5-bis(4-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@H]2O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN([C@@H]2CCCC[C@H]2OCc2ccccc2)C1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of tert-butyl [(3R)-1-(trans-2-hydroxycyclohexyl)pyrrolidin-3-yl]carbamate (0.70 g, 2.46 mmol) and 60% NaH (0.108 g, 2.71 mmol) in DMF (5 mL) at 0° C. was added benzyl bromide (0.79 mL, 2.71 mmol). After being stirred overnight under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to 10% MeOH/EtOAc) to give 0.60 g of the title compound. MS (EI) calcd: (M+H)+=375.3; found: 375.4.
Reaction SMILES: C([O:8][C:9]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:10]=1[CH2:11][N:12]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][N:14]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1)[CH2:28][N:12]([CH2:11][C:10]1[CH:43]=[C:44]([C:47]([F:50])([F:49])[F:48])[CH:45]=[CH:46][C:9]=1[OH:8])[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:18]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Crude ethyl 4-{2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (11.3 g) is dissolved in ethanol (100 ml) and thereto is added 10% palladium-carbon (3 g), and the mixture is stirred under hydrogen atmosphere at room temperature for 2 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (6.03 g). MS (m/z): 626 [M+H]+
Reaction SMILES: [CH2:1](NCCCC)CCC.C(O)(=O)C.C=O.[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH:19]=[O:20]>C1(C)C=CC=CC=1>[CH3:16][CH:17]([CH:21]([CH3:23])[CH3:22])[C:18](=[CH2:1])[CH:19]=[O:20]
Reactant: CC(C)C(C)CC=O
Reactant: CCCCNCCCC
Agent: C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(C=O)C(C)C(C)C
Temperature: 70 °C

Procedure:
Dibutylamine (34 g), acetic acid (15.78 g), and formaldehyde (230 g) were charged to a reaction flask and heated to 70° C. 3,4-Dimethyl-pentanal (500 g) was fed over 2 hours and aged for another hour. The reaction mixture was cooled down and toluene (200 mL) was added. The reaction mixture was sequentially washed with water (2 L), sodium carbonate solution (1 L), and brine (1 L) to provide the crude product 3,4-dimethyl-2-methylene-pentanal.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].CO>O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[OH:11])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2F)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(C(O)c2ccccc2F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
1.61 Parts of sodium tetrahydroborate were added dropwise to a stirred solution of 11 parts of (4-amino-3-nitrophenyl) (2-fluorophenyl)methanone in 120 parts of methanol. Upon complete addition, stirring was continued for 1 hour at room temperature. The reaction mixture was poured into water and the product was extracted three times with 75 parts of trichloromethane. The combined extracts were dried, filtered and evaporated, yielding 11.3 parts (100%) of 4-amino-α-(2-fluorophenyl)-3-nitrobenzenemethanol as a residue (interm. 26).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36].C[O-].[Na+:40]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[CH2:22]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O-:37])=[O:36].[Na+:40]
Reactant: O=C(NC1CCCC(c2ccc(Cl)cc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1CCCC(c2ccc(Cl)cc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.032 g, 0.0592 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.121 ml, 0.0604 mmol), and the reaction was stirred overnight. The reaction was concentrated to yield 33 mg of the title compound (99.1% yield). MS (apci) m/z=540.0 (M-Na+2H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
HCl (10 ml, 4M solution in dioxane) was added in one portion to a stirred solution of 4-benzyloxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.6 mmol) in dioxane (5 ml) and the suspension was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum and the resulting solid was collected by filtration, washed with TBME (3×100 ml) and dried under vacuum to give the title compound (0.74 g, 88% yield) as a white solid. Tr=1.03 min m/z (ES+) (M+H+) 236.
Reaction SMILES: [CH2:1]([NH:4][CH3:5])[CH:2]=[CH2:3].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:4]([CH2:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCNC
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN(C)Cc1csc(N)n1

Procedure:
N-allyl-N-methylamine (7.0 mg, 0.1 mmol), 2-amino-4-chloromethylthiazole hydrochloride (18.5 mg, 0.1 mmol), and potassium carbonate (30 mg, 0.21 mmol) are shaken in ethanol (1 mL) at room temperature for 18 hours. The mixture is filtered and the filtrate was condensed under vacuum.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=3[C:7]3([O:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:6]=12.N1C=CC=CC=1.C(Cl)Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][C:10]([NH:14][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:9][C:8]=3[C:7]3([O:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:6]=12
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12)c1ccccc1
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a cold solution of 3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-amine (0.290 g, 1.44 mmol) and pyridine (0.349 mL, 4.32 mmol, 3 eq) in anhyd. CH2Cl2 (14.4 mL) was added benzoyl chloride (0.200 mL, 1.73 mmol, 1.2 eq) drop-wise with cooling in an ice bath under a dry N2 atmosphere. After stirring 2 hr. at room temperature the reaction was added to water. The reaction mixture was washed with Et2O (3×), basified with 2.5N NaOH and extracted with EtOAc (4×). The combined organic extracts were concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3O H/NH4OH (98/1/1) to give the title compound as a yellow solid (0.079 g, 15% yield). NM (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: Br
Product: Nc1nc2ccc(O)cc2s1
Temperature: 25 °C

Procedure:
2-Amino-6-methoxybenzothiazole is reacted with hot aqueous HBr for about 3 hrs and then the clear solution is cooled to ambient temperature overnight. The precipitated solids are collected, dissolved in hot water and the pH is adjusted to between 4.5-5.5. The resultant solids are collected, dried and recrystallized from Isopropanol. Second crop material is collected. The solids are vacuum dried to give Intermediate 1.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1.Br[CH2:15][CH2:16]Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:3][C:4]1[N:9]=[C:8]([Cl:10])[C:7]([C:11]2([C:12]#[N:13])[CH2:16][CH2:15]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)nc1Cl
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: N#CC1(c2ccc(Br)nc2Cl)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of NaOH (2.59 g, 64.8 mmol) in water (6 mL) was added 2-(6-bromo-2-chloropyridin-3-yl)acetonitrile (1.5 g, 6.48 mmol), tetrabutyl ammonium bromide (0.418 g, 1.296 mmol) and 1-bromo-2-chloroethane (1.079 mL, 12.96 mmol). The resulting mixture was heated to 50° C. and stirred for 2 h, extracted with ethyl acetate (2×30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using column chromtography (eluted with 0-20% ethyl acetate in hexane) to give 1-(6-bromo-2-chloropyridin-3-yl)cyclopropanecarbonitrile (850 mg, yield: 51%) MS (M+H)+: 258.