Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:23]#[N:24])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]([Sn](CCCC)(CCCC)CCCC)=[N+:41]=[N-:42]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:25][C:26]2[CH:27]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=2)[C:23]2[N:40]=[N:41][NH:42][N:24]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.61 mmol) in toluene (10 mL), add azidotributyltin (3.22 mmol) and heat to 100° C. After stirring for 12 h, cool the reaction to room temperature and quench with methanol (1 mL). Dilute the reaction mixture with ethyl acetate (100 mL) and wash with aqueous sodium fluoride (50 mL) and brine (50 mL). Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with methanol/dichloromethane (1-5%) to afford the title compound as a colorless foam. MS (ES+): 597.3 (M−H).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][CH3:11])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([F:9])[N:8]=1
Reactant: N
Reactant: COc1cc(F)nc(F)n1
Solvent: COC(C)(C)C
Product: COc1cc(F)nc(N)n1
Reaction time: 2 h

Procedure:
13.6 g (0.8 mol) of ammonia in 30 ml of methyl tert.-butyl ether were added at -20° to -10° C. to a stirred mixture of 52 g (0.356 mol) of 2,4-difluoro-6-methoxypyrimidine in 300 ml of methyl tert.-butyl ether within 20 minutes. After a further 2 hours at -15° C. and 3 hours at 25° C., the precipitate was filtered off with suction, washed with methyl tert.-butyl ether, stirred with water, filtered off, washed again and subsequently dried, resulting in 36.1 g (71% of theory) of the title compound of melting point 171°-173° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[CH:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:8]=[C:7]1[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:5])=[O:4].[CH:28]([N-]C(C)C)(C)C.[Li+].CI.O>O1CCCC1>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH3:28])[N:8]=[C:7]1[Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])(=[O:5])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CN(C)S(=O)(=O)n1cc(Cc2cccc(F)c2F)nc1[Si](C)(C)C(C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1cccc(F)c1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
An amount of 2.9 g (7.0 mmol) of 2-(tert-butyl-dimethyl-silanyl)-4-(2,3-difluoro-benzyl)-imidazole-1-sulfonic acid dimethylamide was dissolved in 30 ml tetrahydrofuran and added drop-wise to a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (from 6.54 ml 1.6M BuLi and 1.06 g diisopropylamine). After stirring for 1 h at −75° C., 1.14 g (8.0 mmol) methyl iodide was added, and stirring was continued overnight at ambient temperature. Water was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (3 times) and the combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate 4:1) to yield 2.47 g of rac-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide (MS (ISP): 430.3 ((M+H)+.), light yellow oil). This material was separated by chiral column chromatography (Chiral OD, isopropanol/heptane=2:98) to yield 0.785 g (26%) of (+)-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide and 0.946 g (32%) of (+)-2-(tert-butyl-dimethyl-silanyl)-4-[1-(2,3-difluoro-phenyl)-ethyl]-imidazole-1-sulfonic acid dimethylamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[C:5]#[N:6].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]=3[CH2:36][CH3:37])[N:28]=[CH:27]2)[CH:20]=1>>[C:10]([C:8]1[CH:7]=[C:4]([C:5]#[N:6])[C:3]([O:14][CH3:15])=[C:2]([NH:1][C:18](=[O:17])[C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([N:26]3[CH:30]=[C:29]([C:31]4[CH:32]=[N:33][N:34]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:35]=4[CH2:36][CH3:37])[N:28]=[CH:27]3)[CH:20]=2)[CH:9]=1)([CH3:12])([CH3:11])[CH3:13]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C#N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(C#N)c4OC)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 155 was prepared from 3-amino-5-tert-butyl-2-methoxy-benzonitrile and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 559 [C34H34N6O2+H]+.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.[F:13][C:14]([F:22])([F:21])[C:15]([C:17]([F:20])([F:19])[F:18])=[O:16]>O1CCCC1>[F:13][C:14]([F:22])([F:21])[C:15]([OH:16])([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=Cc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A 5 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple thermometer, addition funnel with a nitrogen bubbler, and a cooling bath container. The nitrogen-flushed flask was charged with 200 mL anhydrous tetrahydrofuran, 67.5 g (2.77 mol) of magnesium turnings, and a small crystal of iodine. The addition funnel was charged with 500 g (2.73 mol) of freshly distilled 4-bromostyrene. Approximately 10 mL of 4-bromostyrene was added to the flask with vigorous stirring. As soon as the Grignard reaction was started, the flask was charged with an additional 1800 mL of anhydrous tetrahydrofuran. The remainder of the 4-bromostyrene was added dropwise to the stirred reaction at such a rate as to maintain the reaction at a temperature of 40° C. while cooling the flask with an ice/water bath. The addition required 2 hours, after which the cooling bath was removed and the reaction stirred another 1.5 hours. The reaction mixture was then cooled to 0° C. with a dry-ice/acetone bath, and the addition funnel was replaced with a gas inlet tube connected with appropriate back-flow safeguards to a cylinder of hexafluoroacetone. Hexafluoroacetone gas was passed into the reaction mixture over 2 hours while maintaining the reaction temperature below 15° C. with the cooling bath. After the reaction exotherm diminished, the gas addition was stopped. A total of 480 g (2.89 mol) hexafluoroacetone had been added. The cooling bath was removed and the reaction stirred overnight. The reaction was maintained below 10° C. as 500 mL of 6 N hydrochloric acid was added dropwise with stirring over 1 hour. The organic layer was separated and the aqueous layer extracted with three 300 mL portions of diethyl ether. The combined organic layers were washed with three 300 mL portions of brine, dried over sodium sulfate, filtered, and evaporated on the rotary evaporator. The residue was distilled under vacuum collecting fractions 58-78° C. at a vacuum of 800-300 mTorr. A total of 589 g (74%) of product containing approximately 15 mol % complexed tetrahydrofuran (THF) was obtained.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.C([O-])=O.[NH4+].C(Cl)Cl.CCOC(C)=O.CCOCC.CCCCCC>CO.[Pd]>[CH2:8]1[O:9][C:10]2[CH:11]=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[C:16](=[O:17])[CH:7]1[C:6]1[CH:1]=[CH:2][C:3]([OH:19])=[CH:4][CH:5]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1c2ccc(O)cc2OCC1c1ccc(O)cc1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of daidzein (0.657 g, 2.58 mmol) in methanol (60 mL) was added 10% Pd/C (0.657 g) carefully, following by ammonium formate (0.652 g, 10.3 mmol). The mixture was heated up to 50–60° C. and stirred for one hour. The reaction was monitored by TLC (CH2Cl2/EtOAc=7:2 or 70% Et2O/Hexane) and GC. After the reaction complete, the Pd/C was filtered and the filtrate was concentrated, which gave a crude product (0.558 g) of dihydrodaidzein as the major product and the trans/cis isomers of tetrahydrodaidzein as the minor products. The dihydrodaidzein was purified by standard procedures.
Reaction SMILES: [O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[C:16]([C:17](O)=[O:18])[C:9]=12)[CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[O:1]=[C:2]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[C@@H:3]([N:6]1[C:17](=[O:18])[C:16]2=[CH:15][NH:14][C:10]3[C:9]2=[C:8]([CH:13]=[CH:12][N:11]=3)[CH2:7]1)[CH2:4][CH3:5]
Reactant: CC[C@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@@H](C(=O)N1CCCC1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 49.8 %

Procedure:
Into a 8 mL scintillation vial equipped for stirring was added (S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (6 mg, 0.018 mmol). N,N-dimethylformamide (2 mL), HATU (8.29 mg, 0.022 mmol) and 4-methylmorpholine (2.2 mg, 0.022 mmol) were added and the solution was allowed to stir at room temperature for 1 h. The solvent was removed and the resulting residue was further purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow solid (2.8 mg, 49.4%). 1H NMR (500 MHz, CD3OD) δ 0.97 (t, J=7.32 Hz, 3 H) 1.74-1.98 (m, 5 H) 1.98-2.14 (m, 1 H) 3.08-3.22 (m, 1 H) 3.37-3.47 (m, 1 H) 3.65-3.77 (m, 1 H) 4.07 (s, 1 H) 5.05 (s, 2 H) 5.62 (dd, J=8.54, 7.08 Hz, 1 H) 7.11 (d, J=4.88 Hz, 1 H) 7.80 (s, 1 H) 8.29 (br. s., 1 H). [M+H] calc'd for C17H20N4O2, 313; found, 313.6.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])=[CH:18][CH:17]=3)=[C:11]([CH2:29][CH2:30][CH3:31])[N:10]3[N:32]=[CH:33][N:34]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[S:20][C:19]([C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])=[CH:18][CH:17]=3)=[C:11]([CH2:29][CH2:30][CH3:31])[N:10]3[N:32]=[CH:33][N:34]=[C:9]23)[CH2:4][CH2:3]1)[CH3:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}thiophen-2-yl)benzonitrile (0.4 g), rhodium(I) acetate (0.0019 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.46 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH4+:15].[OH-]>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
A 0° C. solution of 4-chloro-3-nitrobenzenesulfonyl chloride (12.8 g, 50.0 mmol) in diethyl ether (1 L) was slowly treated with 0° C. concentrated NH4OH (50 mL) and stirred for 30 minutes. The organic layer was dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [ClH:1].NC(=O)[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1C=C[CH:8]=[CH:7][CH:6]=1.C1(N)CCCC1>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8]3)=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Agent: NC1CCCC1
Product: Nc1cc(Oc2ccc(NC(=O)CC(=O)NC3CCCC3)cc2F)ccn1
Yield: 44 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with cyclopentanamine (Aldrich, 17 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-cyclopentylmalonamide, hydrochloride salt (18 mg, 44% yield). 1H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.66 (s, 1H), 8.15 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 2H), 6.70 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 3.98 (m, 1H), 3.69 (s, 2H), 1.78 (m, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.37 (m, 2H); MS(ESI+) m/z 373.30 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]5[CH2:28][CH3:29])=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:37])[CH2:24][C@@H:23]5[CH2:28][CH3:29])=[N:19][C:18]4=[O:30])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:3]=1
Reactant: CC[C@H]1CNCCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C=O
Product: CC[C@H]1CN(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2-ethyl-4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-((2S)-2-ethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one and formaldehyde following procedure used as in example 195.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11](Cl)(=[O:14])[CH2:12][CH3:13].O.O.CN(C=O)C>CN(C=O)C>[C:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])(=[O:14])[CH2:12][CH3:13]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.2 %

Procedure:
To a room temperature solution of 50.22 g anthranilic acid (I) (370 mmol, 1.00 equiv) dissolved in 200 mL dry DMF was added 35.0 mL propionyl chloride (400 mmol, 1.10 equiv) dropwise by addition funnel over 1.5 h. The addition rate was slow enough to maintain internal temperature of the reaction below 38° C. Upon completed addition of the acid chloride, the heterogeneous reaction mixture was stirred for 2.5 h at ambient temperature and then poured into 1600 mL water. The resulting water/DMF mixture, with white precipitate, was stirred vigorously at ambient temperature for one h, after which time the solid was collected by vacuum filtration, rinsing the solid with cold water (2×100 mL). The product was dried in vacuo over phosphorous pentoxide overnight affording 48.04 g of a white solid. m.p. 120.1° C. 1H NMR (CDCl3) δ1.30 (t, 3H, J=7.4 Hz), 2.52 (q, 2H, J=7.4 Hz), 7.12 (t, 1H, J=7.2 Hz), 7.60 (t, 1H, J=7.1 Hz), 8.13 (d, 1H, J=6.3 Hz), 8.76 (d, 1H, J=7.8 Hz) ppm. MS (ESI−) 192.1 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a well-stirred solution of L-proline (5.75 g, 0.05 mmole) in 2N NaOH (25 ml), 4N NaOH (12.5 ml) and benzoyl chloride (5.8 ml, 0.05 mole) were added dropwise from different drop funnels, maintaining the temperature near 0°-4° C. The mixture after 15 minutes was acidified with 1N HCl. The resulting oil was extracted with CHCl3, the combined organic extract was dried (MgSO4), and the solvent was removed. Ether was added to the residue and the mixture was allowed to stand overnight at 0° C. The crystals of N-benzoyl-L-proline were separated. Yield 3.42 g (60%), m.p. 152°-154° C., [α]D20 -68.5° (c 0.4; CHCl3); Rf 0.13 (Kiesel-gel, CHCl3 --CH3OH, 9:1). Analysis Calcd. for C12H13NO3 : C, 65.73; H, 5.99; N, 6.39. Found: C, 65.64; H, 6.03; N, 6.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:29][C:28]=1[F:27]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 5, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=534.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:23])[C:18]([C:24]#[N:25])=[CH:17]2.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.CC([O-])(C)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[NH:3][C@H:4]2[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:23])[C:18]([C:24]#[N:25])=[CH:17]3)[CH2:11]1
Reactant: Cn1c(C#N)cc2cc(Br)ccc21
Reactant: CC1(C)CN[C@H]2CCCC[C@H]2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C#N)cc2cc(N3CC(C)(C)N[C@@H]4CCCC[C@@H]43)ccc21
Temperature: 25 °C
Yield: 46 %

Procedure:
A toluene (4 ml) suspension of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (168 mg, 0.998 mmol), 5-bromo-1-methyl-1H-indole-2-carbonitrile (259 mg, 1.10 mmol), Pd(OAc)2 (11.2 mg, 0.0499 mmol), t-Bu3P.HBF4 (14.5 mg, 0.0500 mmol), and NaOt-Bu (135 mg, 1.40 mmol) was stirred for 4 hours under reflux in a nitrogen atmosphere. The reaction solution was cooled to room temperature. Then, water (0.5 mL) and AcOEt (10 mL) were added thereto, and the mixture was stirred. MgSO4 was further added thereto, and the mixture was stirred. Insoluble matter was filtered through celite, and the residue was washed with CH2Cl2:MeOH (3:1) (5 mL×2). Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (Hex-AcOEt) to obtain a colorless oil. This oil was crystallized from hexane (1 mL) to obtain 5-((4aR,8aS)-3,3-dimethyldecahydroquinoxalin-1-yl)-1-methyl-1H-indole-2-carbonitrile (148 mg, yield: 46%) in a pale yellow powder form.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1.[CH3:36][C:37]1[C:42]([CH2:43]Cl)=[CH:41][CH:40]=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>>[CH3:43][C:42]1[C:37]([CH2:36][N:1]2[CH2:6][CH2:5][CH:4]([O:7][C:8]3[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]4[CH2:18][CH2:19][CH:20]([N:23]5[C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[CH2:26][CH2:25][C:24]5=[O:33])[CH2:21][CH2:22]4)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=3)[CH2:3][CH2:2]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: Cc1ncccc1CCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(Cc3ncccc3C)CC2)ccc1CC(=O)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 50 °C

Procedure:
To a solution of 1-(1-(4-(4-piperidinyloxy)-2-methoxyphenylacetyl)piperidin-4-yl)-3,4-dihydro-2(1H)-quinolinone (200 mg, 0.34 mmol) from Example 195 in dry degassed DMF (5 mL) was added 2-methyl-3-chloromethylpyridine (100 mg, 0.68 mmol) and DIEA (0.10 mL, 0.66 mmol) and the reaction was warmed to 50° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using 98:2 CH2Cl2 :MeOH as eluant. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was lyophilized from acetonitrile-water to give the title compound as an amorphous solid.