Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.CCCCCC>C1(C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:6]1[C:5](=[O:4])[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH:18]=[CH2:19]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: C=CCc1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A solution of 4-allyloxy-8-nitroquinoline (3.72 g) in biphenyl (2.59 g) and diphenyl ether (7.4 g) was heated at 200° C. for 10 minutes. After cooling, n-hexane (40 ml) was added thereto, and the mixture was warmed at 90° C. After cooling, the resulting precipitate was collected by filtration to give 3-allyl-1,4-dihydro-8-nitro-4-oxoquinoline (3.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].N1C=CC=CC=1>C(#N)C>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(Cl)cc2)cc1
Yield: 89.5 %

Procedure:
4-Chlorothiophenol (21.6 g) was dissolved in dry acetonitrile (500 ml) and a solution of 4-acetoxybenzoyl chloride (29.7 g) in acetonitrile (50 ml) was added. The mixture was stirred at room temperature whilst pyridine (12.1 ml) was added rapidly dropwise. When the reaction was complete the bulk of the solvents was removed by evaporation in vacuo and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulphate, and evaporated to afford the desired thioester as a pale yellow solid (41.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH3:38][NH:39][CH3:40]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:39]([CH3:40])[CH3:38])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 101) (226 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as a light brown solid (134 mg, 56%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[NH:20]1[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:21]1=[O:27]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][C:21]2=[O:27])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: Cl
Product: O=c1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)[nH]1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and pyrimidine-2,4(1H,3H)-dione. M/e+ 353 for C18H14ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.33 (d, J=5.8 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.39 (td, J=6.9, 1.1 Hz, 1H), 7.00 (td, J=6.9, 1.1 Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 5.58 (d, J=8.0 Hz, 1H), 5.45 (s, 2H) ppm.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]=[C:54]1[NH:58][C@H:57]([C:59](O)=[O:60])[CH2:56][CH2:55]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:59]([C@@H:57]4[CH2:56][CH2:55][C:54](=[O:53])[NH:58]4)=[O:60])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)[C@@H]1CCC(=O)N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a DCM (10 ml) solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.45 g, 1.17 mmol) and HBTU (0.44 g, 1.17 mmol) cooled at 0° C. was added a solution of (S)-5-oxopyrrolidine-2-carboxylic acid (0.15 g, 1.17 mmol) in DMF (5 ml), followed by the addition of DIEA (0.14 g, 1.17 mmol). The reaction was then stirred at room temperature for 1 hour and quenched with 20 ml of aqueous NaHCO3, and extracted with DCM (2×30 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=20:1) to give the title compound (0.30 g, 51%). 1H NMR (400 MHz, CD3OD) δ 7.35-7.32 (m, 2H), 7.10 (d, J=10.9 Hz, 1H), 7.00-6.96 (m, 2H), 5.80-5.65 (br s, 1H), 5.06-5.05 (m, 1H), 4.30-4.15 (m, 3H), 2.45-2.24 (m, 3H), 2.05-2.00 (m, 1H), 1.85-1.80 (m, 1H), 1.48 (d, J=6.8 Hz, 3H), 0.91-0.89 (m, 2H), 0.63-0.62 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[OH:13][C:14]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].[ClH:30]>CS(C)=O.C(Cl)Cl>[Cl:30][C:5]1[CH:6]=[C:7]([O:23][C:20]2[CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]([OH:13])=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: Cl
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1O
Temperature: 25 °C
Reaction time: 30 h
Yield: 91.3 %

Procedure:
A mixture of 3-chloro-4-fluoro-α,α,α-trifluorotoluene (103 g, 0.52 mol), 2,5-dihydroxybenzoic acid (80 g, 0.52 mol) and potassium carbonate (180 g, 1.3 mol) in dimethyl sulfoxide is heated to and held at 130° C. for about 30 hours, cooled to room temperature and poured into ice-water. The aqueous mixture is acidified to pH 2 with concentrated hydrochloric acid and decanted to obtain an oil. The oil is dissolved in methylene chloride, washed with water and concentrated in vacuo to form a brown oil which is crystallized from ether to give the title product as a tan solid (158 g, 91.3%, mp 135° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:27]3[CH2:28][CH2:29][CH2:30][CH:25]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=4)[C:26]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2Cl)cn1
Solvent: CCO
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2Cl)cn1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A suspension of [3-chloro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (66.7 mg, 0.25 mmol) and of 2-bromo-6-phenyl-cyclohexanone (63.3 mg, 0.25 mmol) in ethanol (4 mL) was stirred at room temperature for 30 minutes and then heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified on silica gel with dichloromethane and then with dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (50 mg, 48%) as a pale-brown solid. MS ISP (m/e): 421.0/422.2 (100/38) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.38 (s, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.46-7.10 (m, 7H), 6.98 (s, 1H), 4.03 (m, 1H), 2.72 (m, 2H), 2.13 (s, 3H), 2.11 (m, 1H), 1.70-1.90 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].O.[C:15]1(C)[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C(CC(=O)C)C(C)=O.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[N:4]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:20]1[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(=O)CCC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 811.4 %

Procedure:
To a refluxing solution of 9.20 g (40.0 mmoles) of 2,6-dichloro-4-trifluoromethylaniline and 0.76 g (4.0 mmoles) of p-toluenesulfonic acid monohydrate in 25 mL of benzene was added dropwise over an 8 hour period with a syringe pump 9.40 mL (9.14 g, 80.1 mmoles) of acetonylacetone. Throughout the addition, water was removed via a Dean-Stark trap. The reaction mixture was then cooled and partitioned with a saturated aqueous solution of NaHCO3 which was back-extracted with ether. The combined organic layers were dried over anhydrous Na2SO4 concentrated. The residual brown oil was chromatographed on silica gel with a 95:5 v/v hexane-EtOAc eluent to afford 10.0 g (81%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethylpyrrole as a light brown solid of melting point 63° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[C:20]([O-])([O-:22])=[O:21].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]([O:22][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:21])[CH2:6][CH2:5]2
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2c(c1)CCN2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCCN1CCCC1)N1CCc2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
1.00 g (4.95 mmol) 5-bromoindoline is added to a solution of 868 mg (5.00 mmol) N-(2-chloroethyl)-pyrrolidine hydrochloride and 1.70 g (12.2 mmol) K2CO3 in 15 mL DMF. The reaction solution is stirred for 4 h at 70° C. and more N-(2-chloroethyl)-pyrrolidine hydrochloride is added. The reaction solution is stirred for a further 3 h at 70° C. and then diluted with 25 mL water. The aqueous phase is extracted twice with 30 mL EtOAc. The organic phase is washed with saturated NaCl solution, dried over Na2SO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: EtOAc/MeOH 9:1 to EtOAc/MeOH 4:1).
Reaction SMILES: C([Al:5](CC(C)C)CC(C)C)C(C)C.[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])(=[O:16])[CH3:15]>C1C=CC=CC=1>[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[Al+3:5]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: c1ccccc1
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Product: [Al+3]
Reaction time: 2 h
Yield: 89.6 %

Procedure:
3.96 g of tri-isobutyl aluminum were dissolved in 150 ml of benzene, and a solution of 10.8 g of o-acetoxybenzoic acid dissolved in 200 ml of benzene was added dropwise little by little under ice cooling to the above solution under nitrogen gas current. After completion of the dropwise addition, the temperature of the mixture was returned to room temperature, and the reaction was further continued for 2 hours under agitation. Then, the benzene was distilled off under reduced pressure. Thus, 10.1 g of aluminum tris-(o-acetoxybenzoate) having a melting point above 136° C. were obtained. The resulting aluminum salt had a molecular weight of about 790, and the average degree of polymerization was found to be about 1.4. The infrared absorption spectrum of the salt was as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.O.N.P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:17])[CH:8]=[CH:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cccc(Br)c2[nH]1
Agent: N
Solvent: O
Product: Clc1ccc2cccc(Br)c2n1

Procedure:
A suspension of 2.8 g (12.49 mmol) of 8-bromo-1H-quinoline-2-one in 20 ml of phosphorus oxychloride is refluxed for 90 minutes and the reaction mixture is cooled and then added dropwise to 200 ml of water. The aqueous solution is made basic with concentrated ammonia solution, the precipitate formed is filtered off and washed with water.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.CC1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cc1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)NCCN(C)C)CC2)cc1
Yield: 47 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 1.9 g (0.01 mole) of 1,1'-carbonyldiimidazole, 1.0 g (0.01 mole) of unsym-dimethylethylenediamine, and 2.0 g (0.1 mole) of 1-(4-methylphenyl)piperazine in a total volume of 100 ml of tetrahydrofuran gave an oil which solidified. The solid was triturated with petroleum ether (30°-60° C.) to give 1.5 g (47%) of the title compound as a white solid, m.p. 85°-88° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:21][CH2:22][CH2:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:21][CH2:22][CH2:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1C
Yield: 44.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-propoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (114b) (0.67 g, 1.98 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.22 g of the title compound as a colorless amorphous solid (44%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([I:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O.C(OCC)(=O)C>[I:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=1
Reactant: Cc1ccc2c(Cl)nccc2c1I
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Temperature: 170 °C
Yield: 73.5 %

Procedure:
1-Chloro-5-iodo-6-methylisoquinoline (0.250 g, 0.824 mmol), 3-(trifluoromethyl)phenol (0.200 g, 1.24 mmol), cesium carbonate (0.590 g, 1.81 mmol) were all placed in a clear microwave vial along with 3 ml of DMSO. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 170° C. for 20 minutes. The reaction was diluted with water and ethyl acetate. The organic layer washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 60-100% EtOAc in hexanes to give 5-iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.260 g, 73.6% yield) as a white solid. MS (M+H)+ 430.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1([C:39]([CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:29]([C:28]1[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:33])=[CH:22][CH:21]=2)=[N:24][CH:25]=[C:26]([CH2:31][N:45]2[CH2:44][CH2:43][N:42]([CH2:41][C:39](=[O:40])[N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:47][CH2:46]2)[CH:27]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCN(CC(=O)N4CCCC4)CC3)cc2C#N)cc1
Reaction time: 3 h
Yield: 70.9 %

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (0.3 g, prepared as described in Method 15 below) and 1-(pyrrolidinocarbonylmethyl)piperazine (0.14 g) were dissolved in dichloromethane (10 ml). Sodium triacetoxyborohydride (0.15 g) was added, and the mixture stirred for 3 hours before being washed with water (10 ml). The organic residues were separated and purified using flash column chromatography eluting with ethyl acetate, followed by (6-8%) MeOH in dichloromethane to give t-butyl (2-{[4-(3-cyano-5-{[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]methyl}pyridin-2-yl)benzoyl]amino}phenyl)carbamate (300 mg) as a pale yellow oil. The oil was dissolved in methanol (10 ml), and a 4M solution of hydrogen chloride in 1,4-dioxan (10 ml) added and the solution stirred at ambient temperature for 2 hours. The solvent was evaporated, methanol (5 ml) added and the resulting solution absorbed onto an SCX-2 column, which was then washed with methanol (2 column volumes) and the product eluted with a 2M solution of ammonia in methanol (2 column volumes). The ammonia/methanol was evaporated to give a foam. This was treated with diethyl ether (20 ml), stirred and filtered to give the product as a white solid (195 mg, 57%); NMR Spectrum: (DMSO-d6 373K) 1.82 (m, 4H), 2.50 (m, 8H), 3.11 (s, 2H), 3.40 (m, 4H), 3.66 (s, 2H), 4.74 (br s, 2H), 6.64 (m, 1H), 6.82 (m, 1H), 6.98 (m, 1H), 7.27 (m, 1H), 7.99 (d, 2H), 8.13 (d, 2H), 8.24 (d, 1H), 8.87 (d, 1H), 9.49 (br s, 1H); Mass Spectrum: M+H+ 524.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8].[CH2:19]([NH:21][CH:22]1[CH2:30][CH2:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH2:23]1)[CH3:20]>>[CH2:19]([N:21]([CH:22]1[CH2:30][CH2:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH2:23]1)[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:8])[CH3:20]
Reactant: CCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)c1ccc2ccccc2c1
Product: CCN(CCCCNC(=O)c1ccc2ccccc2c1)C1CCc2ncsc2C1
Yield: 22 %

Procedure:
Compound 4 is prepared from 2E and 4C as described for 1. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:31])[Cl:1])[CH2:29][F:30])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)thiophen-2-yl)methyl)carbamate (140 mg, 0.238 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL) and the reaction mixture stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue washed with diethyl ether, then dissolved in 10% methanol in CH2Cl2 and evaporated to dryness. Washed with n-pentane and dried under vacuum to give the title compound (56 mg): 1HNMR (400 MHz, DMSO-d6) δ: 4.19-4.21 (m, 1H), 4.24-4.26 (m, 2H), 4.29-4.31 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.67-4.70 (m, 0.5H), 4.87 (bs, 1H), 5.90 (bs, 1H) 6.50 (s, 1H), 7.20 (d, J=3.64 Hz, 1H), 7.39 (d, J=8.24 Hz, 2H), 7.43 (d, J=3.68 Hz, 1H), 7.57 (d, J=8.16 Hz, 2H), 8.20 (bs, 3H), 8.59-8.63 (m, 1H). m/z (CI) 388 [M−H].
Reaction SMILES: [C:1]12([S:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1>>[C:22]1([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][S@:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])[CH2:16]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=[S@](NC1CCN(CCc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanesulfinyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanesulfinamide.
Reaction SMILES: [BH4-].[Na+].Br.[Br:4][C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1.[C:14](O)(=O)[CH3:15]>O1CCCC1>[Br:4][C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][C:7]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: Brc1cc2c(s1)CNCC2
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(Br)sc2C1
Temperature: 0 °C
Yield: 96 %

Procedure:
Sodium borohydride (146 mg, 3.85 mmol) was added to cooled (0° C.) a suspension of 2-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrobromide (230 mg, 0.77 mmol) in acetic acid (1.5 mL) and tetrahydrofuran (2.8 mL). On complete addition the mixture was heated to 60° C. for 3 h. The mixture was allowed to cool to ambient temperature then partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 10 by the addition of 3N sodium hydroxide solution and the layers separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to give the title compound as a yellow oil (181 mg, 96%). 1H NMR (DMSO-D6, 300 MHz): 6.93 (s, 1H), 3.50-3.47 (m, 2H), 3.66-2.46 (m, 6H), 1.05 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=1.79 min, M+H+=246/248.