Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1.CS([C:19]1[N:24]=[CH:23][C:22]2=[CH:25][CH:26]=[C:27]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)[N:21]2[N:20]=1)=O>>[CH3:33][N:31]1[CH:32]=[C:28]([C:27]2[N:21]3[C:22]([CH:23]=[N:24][C:19]([NH:15][C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][CH:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])[CH:10]=4)=[N:20]3)=[CH:25][CH:26]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: CN1CCCC1COc1cccc(N)c1
Product: CN1CCCC1COc1cccc(Nc2ncc3ccc(-c4cnn(C)c4)n3n2)c1

Procedure:
Prepared by following a procedure analagous to Example 251c by using 3-(1-Methyl-pyrrolidin-2-ylmethoxy)-phenylamine and 2-Methanesulfinyl-7-(1-methyl-1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazine. 1H-NMR (DMSO) δ 9.7 (brs, 1H), 9.4 (s, 1H), 8.9 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7 (d, J=4.6 Hz, 1H), 6.9 (d, J=4.6 Hz, 1H), 6.6 (d, J=7.2 Hz, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.9 (s, 3H), 3.8 (m, 1H), 3.6 (m, 1H), 3.1 (m, 1H), 2.9 (s, 3H), 2.2 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H), 1.8 (m, 1H); LC/MS (ESI+): 401 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39]Br)=[CH:34][C:33]=1[O:41][CH3:42])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:11]=4[CH2:10][CH2:9]3)[CH2:2]2)=[CH:34][C:33]=1[O:41][CH3:42])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2
Reactant: COc1cc(CCBr)ccc1OCc1ccccc1
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(CCc3ccc(OCc4ccccc4)c(OC)c3)C1)CC2

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(4-benzyloxy-3-methoxy-phenyl)-ethylbromide analogously to Example 1.
Reaction SMILES: [CH2:1]1[CH2:19][O:18][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)=[CH:5][CH2:4]2)[O:2]1.[H][H]>C(O)C.[Pd]>[CH2:19]1[CH2:1][O:2][C:3]2([CH2:4][CH2:5][CH:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)[CH2:7][CH2:8]2)[O:18]1
Reactant: [H][H]
Reactant: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1F
Agent: [Pd]
Solvent: CCO
Product: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1F
Yield: 94.3 %

Procedure:
1,1-Ethylenedioxy-4-(3,4',5'-trifluorophenyl)-3-cyclohexen (100 g) was dissolved in ethanol (1 l), followed by adding Pd/C (5%) (40 g), stirring the mixture in a hydrogen gas atmosphere to carry out a catalytic reduction, filtering off the catalyst after the reaction, and distilling off the organic layer under reduced pressure, to obtain 1,1-ethylenedioxy4-(3',4',5'-trifluorophenyl)-cyclohexane (95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]=[C:7]([C:9]3(O)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1>ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]=[C:7]([C:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccc(Cl)cc3s2)CC1
Solvent: ClCCl
Product: Clc1ccc2cc(C3=CCNCC3)sc2c1
Yield: 90.5 %

Procedure:
A solution of 1.04 gm (2.83 mMol) 6-chloro-2-(4-hydroxy-1-(tert-butoxycarbonyl)piperidin-4-yl)benzothiophene in 30.0 mL dichloromethane was subjected to the reaction conditions described in Example 51, providing 0.64 gm (90%) of 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzothiophene as a tan powder.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:54]=[CH:53][C:34]([NH:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([NH:44][CH2:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[O:43])[CH2:38][CH2:37]3)=[CH:33][CH:32]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][NH:44][C:42]([N:39]2[CH2:38][CH2:37][CH:36]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=4)=[CH:54][CH:53]=3)[CH2:41][CH2:40]2)=[O:43])=[CH:51][CH:50]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCOc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 86.7 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethoxy)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.125 g, 0.15 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.075 g, 0.13 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[C:28]([C@:30]1([OH:38])[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[C:31]1=[O:37])#[CH:29]>>[OH:38][C@@:30]1([C:28]#[C:29][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:27]=2)[CH2:35][CH2:34][CH2:33][N:32]([CH3:36])[C:31]1=[O:37]
Reactant: C#C[C@]1(O)CCCN(C)C1=O
Reactant: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Product: CN1CCC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)C1=O
Yield: 25.3 %

Procedure:
10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-piperidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 22 mg (25.3%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-3-piperidyl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:12][C:10]([CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:3][CH:4]=1)=[O:11]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: COC(=O)CNc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
A solution of 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (4.69 g, 19.1 mmole, from Preparation 28 (c)), tert-butyl acrylate (11.2 mL, 76.5 mmole), DIEA (6.7 mL, 38.5 mmole), Pd(OAc)2 (215 mg, 1 mmole), and P(o-tol)3 (583 mg, 2 mmole) in propionitrile (100 mL) was purged with Ar, then was heated at reflux. After 18 h, the reaction was allowed to cool to room temperature then was concentrated to dryness. The residue was purified by flash chromatography on silica gel (40% EtOAc/hexane) to give the title compound (5.21 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.62 (dd, 1H), 7.47 (d, J=16.0 Hz, 1H), 6.48 (d, J=8.7 Hz, 1H), 6.17 (d, J=15.9 Hz, 1H), 5.21 (br s, 1H), 4.20 (d, J=5.4 Hz, 2H), 3.79 (s, 3H), 1.52 (s, 1H).
Reaction SMILES: CC(OC([N:8]1[C:12]2[CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][C:21]=4[CH:34]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:35])=O)(C)C.C(OCC)C.[ClH:41]>CO.O1CCOCC1>[ClH:41].[ClH:41].[CH3:35][C:9]1[NH:8][C:12]2[CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:26][CH2:25][CH2:24][NH:23][CH2:22][C:21]=4[CH:34]=3)[CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1nc2ccc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Yield: 93 %

Procedure:
A solution of 1,1-dimethylethyl 7-(1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methyl-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (13.1 g, 27 mmol) in a mixture of methanol (20 mL) and 4 N hydrogen chloride in dioxane (30 mL) was refluxed for 15 min. After cooling to room temperature ethyl ether (100 mL) was added, and the reaction mixture was concentrated. Another portion of ethyl ether (100 mL) was added, the precipitate was filtered off, washed several times with ethyl ether, and dried to give 7-(2-methyl-1H-benzimidazol-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine dihydrochloride (8.9 g, 93% yield) as a light beige solid. 1HNMR (400 MHz, CD3OD): 7.93 (s, 1H), 7.86-7.67 (m, 4H), 7.28 (s, 1H), 4.54 (s, 2H), 4.33-4.23 (m, 2H), 3.65-3.54 (m, 2H), 2.91 (s, 3H); MS (EI) for C17H17N3O: 280 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][CH:22]([F:33])[CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[F:21][CH:22]([F:33])[CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OCC(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OCC(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-(2,2-difluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 406.02 g/mol.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1>>[CH3:12][CH:13]1[NH:14][CH2:15][CH2:16][N:17]([C:9]([C:6]2[NH:5][C:4]3[CH:3]=[CH:2][S:1][C:8]=3[CH:7]=2)=[O:11])[CH2:18]1
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cc2sccc2[nH]1
Product: CC1CN(C(=O)c2cc3sccc3[nH]2)CCN1
Yield: 78 %

Procedure:
4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (50 mg, 0.30 mmol) was coupled with 2-methylpiperazine according to Procedure D to provide the title compound (58 mg, 78%) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C12H15N3OS, 249.09; m/z found, 250.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): 7.33 (d, J=5.3 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.88 (s, 1H), 4.62-4.56 (m, 2H), 3.50-3.20 (m, 5H), 1.36 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].C(O)C.Cl.[N:17]([O-])=[O:18].[Na+]>O>[C:1]([C:5]1[CH:10]=[C:9]([N:17]=[O:18])[C:8]([CH3:11])=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)c(C(C)(C)C)cc1N=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a solution of 2-(tert-butyl)-5-methylphenol (32.9 g, 0.2 mol) in water:ethanol (300 ml, 2:1) was added concentrated hydrochloric acid (20 ml, 0.24 mol) and then cooled to 0° C. To the solution was added dropwise a solution of sodium nitrite (14.5 g, 0.21 mol) in water (40 ml) over 30 minutes. After completing the dropwise addition, the mixture was stirred at the same temperature for 2 hours. The precipitated crystals were collected by a filtration, and washed with a cold water. The resultant crystal was dissolved in an ethyl acetate:THF (9:1) solution, washed with saturated brine, dried over sodium sulfate, and purified by silica gel column chromatography on a small amount of silica gel which was eluted with ethyl acetate. After the solvent was removed under reduced pressure, the residue was suspended in hexane and the crystals were collected by filtration to obtain 31.4 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.[CH3:16][N:17]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18](=[O:38])[C@@H:19]([NH:30]C(OC(C)(C)C)=O)[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1>>[CH3:16][N:17]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18](=[O:38])[C@@H:19]([NH2:30])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 114 %

Procedure:
Cold trifluoroacetic acid (TFA, 4 mL) and 0.36 mL of anisole (3.28 mmol) were added to 1.215 g (2.98 mmol) of N-methyl-N-benzyl-2-(S)-t-butyloxycarbonylamino-3-(3-indolyl)propionamide and the resulting solution was stirred at 0° C. for 15 min. The ice bath was removed and the solution was allowed to warm to room temperature. After 30 min the reaction mixture was concentrated and the residue was partitioned between saturated NaHCO3 and CH2Cl2. The organic layer was washed with brine, dried and concentrated leaving 1.044 g of the title compound which was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([CH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:16]=2[F:27])=S)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:30]#[C:31][NH2:32].[Pb]>C(OCC)(=O)C>[C:31]([N:32]=[C:11]([NH:13][CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:16]=1[F:27])[NH:10][CH2:9][C:8]1[CH:28]=[CH:29][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)#[N:30]
Reactant: N#CN
Reactant: CC(C)(C)c1ccc(CNC(=S)NCc2c(F)ccc(NS(C)(=O)=O)c2F)cc1
Agent: [Pb]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CNC(=NC#N)NCc2c(F)ccc(NS(C)(=O)=O)c2F)cc1
Yield: 78.1 %

Procedure:
1-(4-t-butylbenzyl)-3-(2,6-difluoro-3-methanesulfonylaminobenzyl)thiourea (44 mg) and lead cyanamide (30 mg) were added to ethyl acetate (10 ml) and the mixture was refluxed for 18 hours. The resulting mixture was purified by column-chromatogrphy (hexane/ethyl acetate=1/1) to yield the compound 31-7 (35 mg, 78%).
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](Cl)=[O:18]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=1[F:1])=[O:18]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide was synthesized from 2-fluoro-3-(trifluromethyl)aniline and 3-bromo-4-chlorobenzoyl chloride according to the procedure described in Example 183. 3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide was obtained as a red-orange solid. MS (M−H+) 393.9; Calc'd for C14H7BrClF4NO: 395.
Reaction SMILES: C(OC([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[CH:10]([C:15]1[CH:16]=[N:17][C:18]([F:29])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH:20]=1)[CH2:11]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl.O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[C:15]([CH:10]3[CH2:11][CH:12]4[NH:8][CH:9]3[CH2:14][CH2:13]4)[CH:16]=[N:17][C:18]=2[F:29])=[CH:26][CH:25]=1)#[N:28]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(c1cnc(F)c(-c3ccc(C#N)cc3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(C3CC4CCC3N4)cnc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
Compound 16 (275 mg, 0.7 mmol) was dissolved in anhydrous CH2Cl2 (3 mL) and cooled in an ice-water bath. TFA (3 mL) was added in 30 min. After stirring at room temperature for 1 hr, the mixture was poured into a cold solution of NH4OH in water (1:1). The mixture was then extracted with CH2Cl2. The organic phase was washed with brine then dried over anhydrous Na2SO4 and evaporated to dryness. After flash chromatography on a silica gel column with CH2Cl2-MeOH, the free base was isolated as a clear oil (200 mg, 93%). 1H NMR (CDCl3): δ (ppm) 1.5-1.7 (m, 5H), 1.8-1.9 (m, 1H), 2.84 (dd, 1H, J=5.1, 9.0 Hz), 3.61 (br s, 1H), 3.82 (m, 1H), 7.6-7.8 (m, 4H), 8.09 (dd, 1H, J=2.4, 6.6 Hz), 8.14 (m, 1H). 13C NMR (CDCl3): δ (ppm) 29.6, 30.7, 31.9, 40.9, 44.6, 56.8, 63.2, 112.3, 118.9, 121.5 (d, J=112.2 Hz), 129.9 (d, J=13.2 Hz), 132.7, 139.3, 140.1, 141.6, 146.5 (d, J=57.9 Hz), 157.5, 160.7.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.CCCCCC.[O:18]=[C:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].[Cl-].[NH4+]>C1COCC1>[OH:18][C:19]([C:4]1[S:3][C:2]([CH3:1])=[N:6][CH:5]=1)([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(O)c1cnc(C)s1
Reaction time: 0.5 h

Procedure:
To a solution of 1.5 g of 2-methyl-1,3-thiazole in 20 ml of THF was added 5.5 ml of a 2.76 M n-butyllithium/hexane solution at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 2 ml of ethyl 2-oxopropanoate in 10 ml of THF, followed by stirring at −78° C. for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.05 g of ethyl 2-hydroxy-2-(2-methyl-1,3-thiazol-5-yl)propanoate.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)O)[C@H](CCCC1CCCCC1)C(=O)OC(C)(C)C
Yield: 65.9 %

Procedure:
A solution of 1.0 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvaleric acid in 30 ml of acetic acid was hydrogenated over 300 mg of platinum oxide for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. Final traces of acetic acid were removed by the addition and evaporation of toluene (3×10 ml). Chromatography on silica gel using diethyl ether/hexane (1:7) for the elution followed by evaporation yielded 0.67 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-cyclohexyl-butyl]-4-methylvaleric acid as a white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12]C(=O)C)=[CH:11][C:6]=2[O:5][CH2:4]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CO>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3](=[O:2])[CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: CC(=O)Nc1ccc2c(c1)OCC2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)OCC2=O
Temperature: 0 °C

Procedure:
5 ml of 1 N hydrochloric acid are added to a solution of 500 mg (2.62 mmol) of N-(3-oxo-2,3-dihydro-1-benzofuran-6-yl)acetamide in 5 ml of methanol, and the mixture is heated under reflux for one hour. After cooling, the mixture is added to a mixture of ice-water, saturated sodium bicarbonate solution and ethyl acetate. The organic phase is separated off, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. 318 mg (61% of theory) of the target compound result as brown powder with a purity of 75%.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[ClH:19]>O1CCOCC1>[ClH:19].[F:1][C:2]1[C:7]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: COc1ncc(-c2ccc(C)nc2F)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(F)n1
Yield: 93 %

Procedure:
5-(2-Fluoro-6-methyl-pyridin-3-yl)-2,4-dimethoxy-pyrimidine (Prep114, 691 mg, 2.76 mmol) was dissolved in 4M HCl in dioxane solution (7 ml). After refluxing the reaction mixture for 45 minutes, the solvent was removed under vacuum to give 667 mg of the title compound (93% yield)
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([N+:5]#[N:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1cc(F)c(F)c(Br)c1Cl
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(Br)c1Cl

Procedure:
To a suspension of 3-bromo-2-chloro-4,5-difluoroaniline (30.1 g) in 42% fluoroboric acid (180 ml) with stirring vigorously was added sodium nitrite (12 g) in water (30 ml) at -9° to 1° C. for 40 minutes. After stirred for 1.5 hours, the resulting precipitate was collected by filtration and washed with 42% fluoroboric acid and then with ether to give the title compound (35.6 g) as light yellow needles, mp 300° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH:12]=O)([CH3:6])[CH3:5])#[N:2].[ClH:17].Cl.[C:19]1([C@H:25]2[C@@H:30]([NH2:31])[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.Cl.C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[ClH:17].[ClH:17].[C:1]([CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][NH:31][C@H:30]1[CH2:29][CH2:28][CH2:27][NH:26][C@H:25]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:6])[CH3:5])#[N:2]
Reactant: COc1ccc(C(C)(C)CC#N)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C(C)(C)CC#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 47 and Compound 3 in the same manner of Compound 5.
Reaction SMILES: [Na].[CH3:2][SH:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8](F)=[C:9]([CH:12]=1)[C:10]#[N:11].O>CS(C)=O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:3][CH3:2])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CS
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Cl)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) A 3 M aqueous solution of methyl mercaptan sodium salt (15 ml) was added to a solution of 5-chloro-2-fluorobenzonitrile (5.0 g) in DMSO (100 ml). The resulting mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (200 ml) and the resulting mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water, and dried to give 5-chloro-2-(methylsulfanyl)benzonitrile (4.6 g) as a white solid.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9](=[O:18])[CH2:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]>C(Cl)(Cl)Cl>[CH2:6]([O:8][C:9](=[O:18])[CH:10]([Cl:4])[C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CC(C)(C)C(=O)CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Cl)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sulfuryl chloride (0.84 ml, 10.4 mmol) was added to a cooled (0°) solution of 4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (1.83 g, 9.93 mmol) in chloroform (7 ml). The resulting mixture was allowed to warm to room temperature and stir for 30 min, after which it was heated under reflux for 2 h. After cooling to room temperature the reaction mixture was diluted with chloroform, then was washed with sodium bicarbonate, water then brine. The organic phase was dried and evaporated to afford, as a brown oil, 2-chloro-4,4-dimethyl-3-oxo-hex-5-enoic acid ethyl ester (2.01 g, 93%). (Hayashi et al., J. Org. Chem., 65:8402–8405 (2000).