Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:30][C:31](=[O:39])NC2C=CC=CC=2)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1>>[C:25]([O:24][C:23]([NH:22][CH2:21][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[O:39])=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCC(CC(=O)Nc1ccccc1)c1ccc(Cl)cc1
Product: CCOC(=O)c1ccc(NC(=O)CC(CNC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1
Yield: 72 %

Procedure:
The compound was prepared from 33 and ethyl 4-aminobenzoate in a similar manner as described for preparation of 34. Chromatography on silica gel (7:3 hexanes/ethyl (Rf 0.20) afforded 35 as a brown solid in 72% yield. 1H NMR (400 MHz, CD3OD) δ 1.35 (9H, s, C(CH3), 1.35 (3H, t, J 6.8 Hz, CH2CH3), 2.63 (1H, dd, J 8.6, 14.6 Hz, H—CHCO), 2.77 (1H, dd, J 6.2, 14.6 Hz, H—CHCO), 3.35-3.40 (1H, m, CH2CHCH2), 4.31 (2H, q, J 7.2 Hz, CH2CH3), 7.24 (2H, d, J 8.8 Hz, 2×Ar—H), 7.28 (2H, d, J 8.8 Hz, 2×Ar—H), 7.57 (2H, d, J 8.4 Hz, 2×Ar—H), 7.91 (2H, d, J 9.2 Hz, 2×Ar—H). 13C NMR (400 MHz, CDCl3) δ 14.56 (s) (CH2CH3), 28.56 (s) (C(CH3)3), 40.92 (s) (CH2CO), 42.77 (s) (CH2CHCH2), 45.97 (s) (CH2NH), 61.04 (s) (C(CH3)3), 80.56 (s) (CH2CH3), 119.07 (s) (2×CH, Ar), 125.90 (s) (C, Ar), 129.08 (s) (2×CH, Ar), 129.17 (s) (2×CH, Ar), 130.90 (s) (2×CH, Ar), 133.17 (s) (C, Ar), 140.35 (s) (C, Ar), 142.65 (s) (C, Ar), 157.54 (s) (C═O), 166.47 (s) (C═O), 170.32 (s) (C═O). νmax (pure sample)/(cm−1)), 3353 (md), 1685 (st) (C═O), 1685 (st) (C═O), 1661 (st) (C═O), 1524 (st), 1273 (st), 1249 (st), 1188 (st), 769 (md).
Reaction SMILES: [NH2:1][N+:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[CH3:9].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:37][CH3:38])(=[O:36])[C:30]#[C:31][C:32]([O:34][CH3:35])=[O:33].O>CN(C)C=O>[CH3:8][C:6]1[C:7]2[N:2]([N:1]=[C:30]([C:29]([O:37][CH3:38])=[O:36])[C:31]=2[C:32]([O:34][CH3:35])=[O:33])[C:3]([CH3:9])=[CH:4][N:5]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1c[n+](N)c(C)cn1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(C)cnc(C)c2c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 1-amino-2,5-dimethylpyrazin-1-ium-2,4,6-trimethylbenzenesulfonate (4.72 g, 14.6 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassium carbonate (4.44 g, 32.1 mmol). The mixture was stirred at room temperature for 10 min. Then a solution of dimethyl but-2-ynedioate (1.87 g, 13.2 mmol) in DMF (30 mL) was added. The resulting mixture was stirred at room temperature for 1 h. Then the mixture was poured into water (400 mL), extracted with EtOAc (3×200 in L). The combined organic layer was dried over sodium sulfate, filtered, evaporated, and chromatographed on silica gel using 20% ethyl acetate (EtOAc) in petroleum ether (PE) as eluent to give 1.04 g (27% yield) of the title compound as a yellow solid. ESI MS: m/z 124.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=0.8 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 2.81 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:11])[CH2:8][CH2:9][OH:10].[CH3:18]I.[Mg].S(=O)(=O)(O)O>O.CCOCC.C1COCC1>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:11])([CH3:18])[CH2:8][CH2:9][OH:10]
Reactant: O=C(CCO)c1ccccc1-c1ccccc1
Reactant: CI
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.26 of 1-p-biphenylyl-3-hydroxypropan-1-one (obtainable by acylating biphenyl with 3-methoxypropionyl chloride to give 1-p-biphenylyl-3-methoxypropan-1-one and subsequent ether splitting) in 20 ml. of THF is added dropwise at 20°, with stirring, to a Grignard solution prepared from 3 g. of methyl iodide and 0.5 g. of magnesium in 100 ml. of ether. The mixture is stirred for a further 4 hours, the resulting alcoholate is decomposed by means of water and dilute sulfuric acid, and standard working up gives 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])[CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1NC(=O)C(C)C(=O)O

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(5-fluoro-2-methylphenylamino)-2-methyl-3-oxopropanoate (2.45 g, 9.67 mmol) in THF (10.0 mL). The crude product was used without further purification. Mass Spectrum (ESI) m/e=226.0, (M+1).
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Br[C:22]1[CH:28]=[C:27]([F:29])[C:25]([NH2:26])=[C:24]([F:30])[CH:23]=1.[CH2:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH2:32][CH3:33]>O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:31]([C:34]1[CH:39]=[CH:38][C:37]([C:22]2[CH:28]=[C:27]([F:29])[C:25]([NH2:26])=[C:24]([F:30])[CH:23]=2)=[CH:36][CH:35]=1)[CH2:32][CH3:33]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CCCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1ccc(-c2cc(F)c(N)c(F)c2)cc1
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
348 g trisodiumphosphate dodecahydrate (Merck KGaA, Art. No.106 578) were dissolved in 500 ml of distilled water. Then 8.563 g bis(triphenylphosphine) palladium (Merck KGaA, Art. No. 804 174) and 0.611 g hydaziniumhydroxide (Merck KGaA, Art. No. 804 604) were added. The suspension was stirred for 5 minutes. Then, 126.886 g 4-bromo-2,6-difluoro-aniline, prepared in house, were added. Next 100 g of the p-n-propylphenyl boronic acid, prepared as described above, dissolved in 600 ml dried tetrahydrafurane (Merck KGaA, Art. No.108 107) was added dropwise. The reaction mixture was heated 6 hours under reflux. The organic layer was separated, dried over Na2SO4 and it's solvent evaporated. The isolated crude product (150 g of 4′-n-propyl-3,5-difluoro-biphenyl-4-ylamine was used for the next step of the reaction without further purificatoin.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@:8]([OH:31])([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:30])[CH:17]=3)=[CH:14][N:15]=2)[CH2:7][C:6]1([CH3:33])[CH3:32])=[O:4].[OH-].[Na+].Cl>CO>[OH:31][C@:8]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:30])[CH:17]=3)=[CH:14][N:15]=2)[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[C:6]([CH3:33])([CH3:32])[CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a solution of the product of Step 1 (16.5 g, 35.3 mmol) in methanol (115 mL) was added sodium hydroxide (1M, 123 mL, 123 mmol) and the mixture was heated to 70° C. for 2.5 hours. The reaction was cooled to 30° C. and hydrochloric acid (1 N, 123 mL, 123 mmol) was added. The reaction was aged for 1.5 hours and filtered to provide 15.3 g (33.7 mmol, 96%) of the title compound as a white solid. MS ESI: [M+H]+ m/z 453.0. 1H NMR (600 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.55 (s, 1H), 8.32 (d, J=5.0, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 6.72 (d, J=5.0, 1H), 5.86 (s, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.14 (dd, J=12.7, 3.1, 1H), 2.00 (ddd, J=18.6, 13.2, 6.0, 1H), 1.88-1.77 (m, 3H), 1.62 (d, J=14.1, 1H), 1.55 (dq, J=13.5, 3.3, 1H), 1.09 (s, 3H), 0.97 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][OH:14])[CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>O1CCCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][O:14][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(Nc1cc(Cl)ccc1C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 4-chloro-2-[(3-hydroxy-1-phenylpropyl)amino]benzonitrile (2.3 g, 8 mmol) in dry tetrahydrofuran (50 ml) was treated with tert-butyldimethylsilylchloride (2.41 g, 2 eq.) and imidazole (1.09 g, 2 eq.) and stirred at room temperature for 1 h. The reaction mixture was diluted with water (200 ml) and the products extracted into diethyl ether (200 ml). The organic extract was dried over magnesium sulphate and concentrated to an oil. The crude product was purified on silica gel eluting with isohexane/diethyl ether (2:1) to afford the title compound as a colourless oil (2.3 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([OH:22])=O)=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:41])[CH2:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:22])[NH:41][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:38][CH2:39][CH2:40]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CCC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CCC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.15 mmol) and 1-phenylcyclobutanamine hydrochloride (0.041 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.18 (s, 1H), 8.42 (d, J=4.58 Hz, 1H), 8.14-8.22 (m, 2H), 7.97 (s, 1H), 7.88 (dd, J=16.02, 7.48 Hz, 2H), 7.82 (d, J=8.54 Hz, 1H), 7.66 (dd, J=8.24, 5.80 Hz, 2H), 7.59 (t, J=7.63 Hz, 1H), 7.52 (d, J=7.63 Hz, 2H), 7.31-7.40 (m, 4H), 7.21 (t, J=7.32 Hz, 1H), 2.77 (d, J=4.58 Hz, 3H), 2.62-2.71 (m, 2H), 2.53-2.60 (m, 2H), 2.02-2.11 (m, 1H), 1.83-1.92 (m, 1H). LCMS: retention time: 3.370 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 535 (MH+).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:24]=[CH:23][C:18]2[S:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1.O>CN(C)C=O>[Si:10]([O:14][C:15]1[CH:24]=[CH:23][C:18]2[S:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1oc2cc(O)ccc2s1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2sc(=O)oc2c1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Imidazole (972 mg) and t-butylchlorodimethylsilane (2.15 g) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (2.00 g) in N,N-dimethylformamide (60 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the target product (3.00 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[OH:16][CH2:15][C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][C:11]=2[CH:12]=1
Reactant: O=C(O)c1cc2cc(-c3ccccc3)ccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 61.8 %

Procedure:
A solution of 5-phenyl-benzofuran-2-carboxylic acid 16 (2.1 g, 8.8 mmole) dissolved in THF (50 ml) was cooled to 50° C. in an ice bath, and LiAlH4 (0.67 g, 17.6 mmole) was added portionwise and stirred at room temperature for 1.5 hrs. The excess reagent was decomposed with an addition of 1M HCl, and the acidified mixture was extracted with ethyl acetate, washed, dried, and evaporated. The residue was purified by chromatography to give about 1.22 g of 2-hydroxymethyl-5-phenyl-benzofuran 17, mp. 134-135° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[Br:13][C:14]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:15]=1[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[Br:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCOc1cc(Cl)ncc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(Br)c(C=O)c2)ncc1C#N
Temperature: 110 °C
Yield: 73.5 %

Procedure:
A mixture of 6-chloro-4-ethoxy-nicotinonitrile (3.80 g, 20.8 mmol), 2-bromo-5-hydroxy-benzaldehyde (4.60 g, 22.9 mmol) and K2CO3 (4.31 g, 31.2 mmol) in dimethyl formamide (30 mL) was heated to 110° C. for 5 hours. The reaction mixture was diluted with H2O (400 mL) and extracted with ethyl acetate (8×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (15-50% ethyl acetate/hexanes) to give the title compound as a white solid (5.31 g, 73%).
Reaction SMILES: C1(=O)[N:5]([C:6]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:12][CH2:13][CH:14]([F:29])[CH:15]([N:18]2C(=O)C3=CC=CC=C3C2=O)[CH:16]=[CH2:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C(=O)C2=CC=CC=C12.O1CCOCC1.C(O)C.Cl.C(O)C.N>C(O)C>[NH2:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH2:12][CH2:13][CH:14]([F:29])[CH:15]([NH2:18])[CH:16]=[CH2:17])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: C=CC(C(F)CCC(C(=O)OCC)(C(=O)OCC)N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: N
Solvent: CCO
Solvent: C1COCCO1
Product: C=CC(N)C(F)CCC(N)(C(=O)OCC)C(=O)OCC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The foregoing compound 22 (17.5 g, 31.8 mmoles) and a 1M solution of N2H4.H2O in dioxane/ethanol 4:1 (35 mL, 2 equivalents) are stirred and heated at about 90° C. After 3 hours, a yellow precipitate is formed, and the mixture is allowed to cool to room temperature. The precipitate is filtered and the filtrate is evaporated to yield an oil. The oil and the precipitate are united and heated with ethanol (310 mL) and conc. HCl (18.6 mL) at 90° C. for 3 hours. After cooling, phthalhydrazide is filtered and the solution is evaporated. Dissolving in water, filtration, evaporation, dissolving in ethanol, evaporating again and drying (oil pump) yields a yellow foam: 11.5 g (about 100%). Thin layer chromatography (ethanol/ammonia 80/20) shows a second spot (presumably some ester cleaved). The compound 23 is utilized for the next step without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]2[CH2:33][CH2:32][CH:31](/[CH:34]=[CH:35]/[CH2:36][OH:37])[CH2:30]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH:29]2[CH2:33][CH2:32][CH:31](/[CH:34]=[CH:35]/[CH:36]=[O:37])[CH2:30]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NC2CCC(/C=C/CO)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)NC2CCC(/C=C/C=O)C2)cc1
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Dimethylsulfoxide (312 mg), oxalyl chloride (254 mg) and triethyl amine (600 mg) were added to the alcohol [prepared in (1)] dissolved in methylene chloride (5 ml). The mixture was stirred for 1 hour at -35° C. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=7:3) to obtain the title compound (405 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:17])=[CH:6][CH:5]=2.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[C:22]([CH3:24])([O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:23])[CH3:19]
Reactant: Cc1[nH]c2ccc(O)cc2c1-c1ccncc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH3:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[N:10]=[C:9]3[CH2:12][CH2:13][CH3:14])[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: CCCc1nc2c(OC)cccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: CCCc1nc2c(OC)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 53.8 %

Procedure:
Using 4-methoxy-2-propyl-1H-benzo[d]imidazole (Journal of Pharmacy and Pharmacology; 1956, vol. 8, p 661, 338 mg, 1.78 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (700 mg, 1.95 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (448 mg, 54%) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:8][N:7]=1)(=[O:33])=[O:32]
Reactant: OCCCOc1ccc(C(F)(F)F)cn1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCOc1ccc(C(F)(F)F)cn1
Reaction time: 1.5 h
Yield: 117.4 %

Procedure:
A mixture of 4.0 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine, 3.4 ml of triethylamine and 25 ml of toluene was vigorously stirred under a nitrogen stream, while cooling in chilled water bath to 5° C. Then, 1.63 g of methanesulfonyl chloride was added dropwise to this mixture at such a rate that the reaction temperature did not exceed 10° C., and the chilled water bath was removed. After further stirring continued at room temperature for 1.5 hours, 250 ml of water was added thereto, and the mixture was vigorously stirred for further 30 minutes, followed by phase separation. The toluene layer was washed once with water, dried with magnesium sulfate, and concentrated, which afforded 5 g of 2-(3-methanesulfonyloxypropyloxy)-5-trifluoromethylpyridine as an oily product (92% yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccnc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 4-pyridin-3-yl-benzoic acid methyl ester (124 mg in 5.0 mL dry methylene chloride) at -78° C. was added 1.46 mL of a 1M solution of diisobutylaluminum hydride in methylene chloride and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of acetone, warmed to room temperature and stirred for 20 minutes with 1.5 mL of a 1M solution of tartaric acid. At this time the mixture was extracted with methylene chloride and the combined organics dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 1:1; then methylene chloride:methanol, 95:5) gave the title compound (104 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]([OH:16])[CH2:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a stirring solution of 34 g (0.15 mole) of 1-[5-(p-chlorophenyl)-2-furyl]-1-propanone in 300 ml of anhydrous methanol was added portionwise 4.1 g (0.11 mole) of NaBH4 while maintaining the temperature between 15°-20°. The reaction solution was stirred at room temperature for 3 hours and after standing over-night was added to ice/water with a solid forming. The solid was filtered and air-dried to yield 34 g (99%) of title compound. An analytical sample was prepared by recrystallizing a sample from hexane/charcoal, m.p. 74°-75°C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCSCc1ccon1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1ccon1)N[N+](=O)[O-]

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isoxazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-isoxazolylmethylthio)ethyl]guanidine.