Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: BrCC1CCCC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CCCC2)C1=O

Procedure:
The title compound was prepared from (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) and (bromomethyl)cyclopentane as described in Example 44, Step A. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:20]=[CH:21][CH:22]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:15][N:16]([C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:17]1[CH:18]=[C:19]([C:23]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CNc1cccc(C(=CCCCC(=O)OC)c2cccnc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)CCc1c[nH]c2ccccc12)c1cccc(C(=CCCCC(=O)O)c2cccnc2)c1

Procedure:
A mixture of 1.9 g of 3-(3-indolyl)-propionic acid, 2.3 g of methyl 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.8 g of carbonyldiimidazole is refluxed for 48 hours in 50 ml of tetrahydrofuran. The reaction mixture is evaporated down, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50° C. for 30 minutes. The reaction mixture is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [CH:1]1([CH:4]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH:1]1([CH:4]([NH:8][C:9]2[C:14]([NH2:15])=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2]1
Reactant: CCCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1N)C1CC1
Yield: 72.2 %

Procedure:
(1-Cyclopropyl-butyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.66 g, 1.74 mmol) and Na2S2O4 (2.45 g, 14.0 mmol) were treated substantially as described in Part E of Example 9 to yield 0.44 g (72%) of N2-(1-cyclopropyl-butyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 350.3 [(M+H)+, 100].
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:6])([CH3:5])[CH3:4]>CCOCC.[Cl-].[Zn+2].[Cl-]>[C:3]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[OH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(Cc1cccc(C(C)(C)C)c1)C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(C)(C)C)c1)C(O)c1cccc(Cl)c1
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a suspension (50 ml) of zinc chloride (3.60 g, 26.4 mmol) in ether was added sodium borohydride (2.0 g, 52.8 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (4.91 g, 13.2 mmol) in ether (40 ml), and the mixture was stirred at room temperature for 1 hr. The reaction was quenched with 1N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1, 3:1) to give ethyl (2RS,3RS)-2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate (4.16 g, 82%) as a colorless transparent oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:40])[NH:38][NH2:39]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([NH:39][NH:38][C:37]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: NNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 1C (1.10 g, 3.65 mmol) in dichloromethane at 0° C. was treated with dicyclohexylcarbodiimide (0.83 g, 4.02 mmol), stirred for 30 minutes, treated with benzyl carbazate (0.69 g, 4.02 mmol), warmed to room temperature, and stirred for 32 hours. The mixture was filtered, and concentrated, and the concentrate was purified by flash column chromatography on silica gel with ethyl acetate in hexanes to provide the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:15]1([C:2]2[N:7]=[CH:6][C:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[O:10][C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc2oc3ccccc3c2cn1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3oc4ccccc4c3cn2)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
3-chlorobenzofuro[3,2-c]pyridine (2.89 g, 14 mmol), phenylboronic acid (2.56 g, 21 mmol), potassium phosphate (9.6 g, 42 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.45 g, 1.12 mmol) and Pd2(bda)3 (0.256 g, 0.28 mmol) were to toluene (100 mL) and water (10 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was washed with ethyl acetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethyl acetate and hexanes as the eluent. The solvent was removed to give 2.77 g of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CCN=C=NCCCN(C)C.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:34]1[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]1)=[O:13])=[CH:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(c1cc2cc(F)ccc2[nH]1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Fluoro-1H-indole-2-carboxylic acid (4.0 g) and EDCI (4.29 g) were combined in dichloromethane (90 mL) and treated with 1-(2-pyridinyl)piperazine (3.64 g). After stirring at 25° C. for 24 hours, the mixture was washed with 150 mL of water and filtered. The filter cake was washed in succession with 300 mL of water, 250 mL of dichloromethane and 20 mL of ethyl acetate to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.61 (m, 4H), 3.85 (m, 4H), 6.67 (dd, 1H, J=7.5, 4.8 Hz), 6.85 (m, 2H), 7.06 (m, 1H), 7.40 (m, 2H), 7.65 (m, 1H), 8.04 (dd, 1H, J=4.5, 1.8 Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[F:48][C:49]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:50]=1[O:51][CH2:52][CH2:53][CH2:54][NH2:55].C(=O)([O-])O.[Na+]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1CN(C)C.[CH-]1C=CC=C1.[Fe+2]>[F:48][C:49]1[CH:59]=[CH:58][C:57]([F:60])=[CH:56][C:50]=1[O:51][CH2:52][CH2:53][CH2:54][NH:55][C:27]1[CH:28]=[CH:29][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:25][CH:26]=1
Reactant: NCCCOc1cc(F)ccc1F
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc21
Agent: CN(C)Cc1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(NCCCOc4cc(F)ccc4F)cc3)cc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A baked-out Schlenk flask is initially charged with 0.350 g of chloro(di-2-norbornylphosphino)(2-dimethylaminomethylferrocen-1-yl)palladium(II). Under argon, a solution of 0.520 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(4-trifluoromethanesulphonyloxyphenyl)piperidine-1-carboxylate (Example 265b) and 0.172 g of 3-(2,5-difluorophenoxy)propylamine in 5.3 ml of dried dioxane is added. The reaction mixture is stirred at room temperature over 30 minutes and subsequently at 100° C. over 18 hours. The reaction mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.29 (2:1 EtOAc-heptane); Rt=4.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:18][O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]4[NH:37][N:36]=[N:35][N:25]=4)=[CH:22][C:21]=3[F:28])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(-c2nnn[nH]2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (example 37.2) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as off-white solid. MS: m/e=521.3 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C)=[C:4]([F:12])[C:3]=1[CH2:13][CH3:14].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:12])[C:3]=1[CH2:13][CH3:14]
Reactant: CCc1c(Cl)ccc(NC(C)=O)c1F
Agent: Cl
Solvent: CO
Product: CCc1c(Cl)ccc(N)c1F

Procedure:
To a solution of N-(4-chloro-3-ethyl-2-fluorophenyl)acetamide (11.0 g, 51.0 mmol) in MeOH (80 mL) is added concentrated HCl (40 mL) before heating at reflux for 16 hours. The solvent is removed from the cooled reaction under reduced pressure maintaining the water bath below 45° C. The residue is cooled with an ice bath before a 3N NaOH solution is added to adjust pH between 9 and 10. The mixture is extracted with ether and dried over MgSO4. The solvent is removed and the residue is purified through a flash chromatography using a gradient of ether/hexanes to give 4-chloro-3-ethyl-2-fluoroaniline.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[CH3:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[CH2:33][C:21]1=2>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:30]2[CH:29]=[CH:28][C:27]3[C:22]4[CH2:23][CH2:24][C:25](=[O:26])[N:20]([CH3:19])[C:21]=4[CH2:33][C:32]=3[CH:31]=2)=[O:11])=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: CN1C(=O)CCC2=C1Cc1ccccc12
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1C(=O)CCC2=C1Cc1cc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under nitrogen, aluminum chloride (2.0 g, 15.06 mmol) is slurried in dichloromethane (100 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (1.28 g, 5.02 mmol) is added and allowed to stir at ambient temperature for 30 minutes. To this mixture 1-methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.0 g, 5.02 mmol) is added in 13 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1 hour. The reaction mixture is poured over ice-water (300 mL) and extracted with dichloromethane, organic separated and concentrated to give crude title compound. Recrystallization from warm methanol afforded the title compound as a yellow powder (1.11 g, 53% yield). 1H NMR (MeOD) δ 2.77-2.83 (m, 4H), 3.28 (s, 3H), 3.59 (s, 2H), 5.17 (s, 2H), 7.19 (d, 1H, J=7.83 Hz), 7.68-7.73 (m, 2H), 7.86 (s, 1H), 7.94 (dd, 1H, J=2.27, 8.33 Hz), 8.46 (d, 1H, J=2.02 Hz), MS (m/z): 417 (M+1). M.P. 259-260° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].N1C=CC=CC=1.[NH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1>O>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH2:27][C:28](=[O:33])[N:29]2[CH3:32])=[CH:24][CH:23]=1)=[O:5]
Reactant: CN1C(=O)CCc2ccc(N)cc21
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3F)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Fluoro-4-(trifluoromethyl)benzoyl chloride was added to a pyridine solution of 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one, followed by stirring at room temperature for 12 hours. Water was added to the reaction liquid, followed by stirring for 30 minutes and then the precipitated crystals were collected by filtration to obtain 2-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-(trifluoromethyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]=1[N+:23]([O-:25])=[O:24])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>O1CCOCC1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:15]2)[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][S:19](=[O:22])[CH2:20][CH2:21]2)[C:5]=1[N+:23]([O-:25])=[O:24])[CH3:2]
Reactant: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: CCOc1nc(N2CCN(C(=O)CCC(=O)O)CC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
3.75 gm (0.01 mol) of 6-ethoxy-5-nitro-4-(1-oxido-thiomorpholino)-2-piperazino-pyrimidine (m.p. 223°-224°C) were refluxed together with 2.0 gm (0.02 mol) of freshly distilled succinic acid anhydride in 50 ml of dioxane for 1 hour. The reaction solution was then evaporated to dryness, and the solid residue was recrystallized from ethyl acetate/isopropanol. Yield: 2.0 gm (42.5% of theory); m.p. 198°-200°C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][C:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>>[OH:26][CH2:25][C:22]1([NH:21][C:18]([C:8]2[CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:11]([N:12]3[CH2:13][C:14]([F:16])([F:17])[CH2:15]3)=[CH:10][N:9]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: NC1(CO)CC1
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Product: O=C(NC1(CO)CC1)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 53e) and (1-aminocyclopropyl)methanol (CAN 107017-72-1) as starting materials and isolated (85 mg, 51%) as a waxy solid; MS (ESI, m/z): 354.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[CH:3]1>C(O)C(C)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:3]3[NH:4][CH2:5][CH2:6][N:2]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(N)ccc21
Solvent: CC(C)CO
Product: Cn1cnc2cc(NC3=NCCN3)ccc21
Yield: 101.8 %

Procedure:
A solution of 1-methyl-5-aminobenzimidazole (0.15 g, 1.1 mmol) and ISA (0.30 g, 2.2 mmol) in 3 ml of isobutanol was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue which was purified on silica gel column chromatography (NH3 sat'd 20% isopropanol/EtOAc) to yield 0.12 g (0.56 mmol, 51%) of the desired product. The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.11 g (30%) of the product as a white crystal: mp 210-211° C.; Anal. Calc. for C11H13N5.1.0C4H4O4-0.3H2O requires C, 35.36; H. 5.28; N,20.74. Found: C, 53.67; H, 5.13; N, 20.70.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)#[N:6]>O1CCCC1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)(=[O:1])[NH2:6]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C#N)ccc2O1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)N=C(c2ccccn2)c2cc(C(N)=O)ccc2O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Aqueous 2N sodium hydroxide solution (6 ml) and 30% hydrogen peroxide solution (8 ml) were added dropwise over 20 minutes to a solution of 6-cyano-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.40 g) in tetrahydrofuran(16 ml). The mixture was stirred at room temperature for 40 minutes. The reaction mixture was extracted by addition of ethyl acetate. The organic layer was successively washed with an aqueous sodium bicarbonate solution, an aqueous sodium bisulfite and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to obtain 6-carbamoyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.30 g) (compound 9).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17](O)=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]([NH:10][C:11]2[C:12]([OH:20])=[N:13][C:14]([C:17]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:18])=[N:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ncc(NC(=O)C(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Step A product, 3-1-a, (300 mg, 0.86 mmol), methyl 2-aminoacetate (129 mg, 1.03 mmol) and DIEA (222 mg, 1.7 mmol) in DMSO (10 mL) was added with TBTU (330 mg, 1.03 mmol) and stirred at room temperature for overnight. The reaction mixture was poured into ice water (100 mL). The solids were filtered and purified by pre-HPLC to afford the product as a white solid, 3-1-b, (60 mg, 17%). LC-MS (M+H)+ 421.0
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[C:55]([O:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][C@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:37]=2[N:36]=[CH:35][CH:34]=[CH:33]3)=[O:25])=[CH:49][CH:50]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 85 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[CH2:8]([NH:10][C:11](=[O:13])[O-:12])[CH3:9].C[O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1>>[CH2:8]([NH:10][C:11](=[O:12])[O-:13])[CH3:9].[OH:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Agent: BrB(Br)Br
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Product: CC1c2ccc(O)cc2C2CNCC12
Reaction time: 8 h

Procedure:
BBr3 in CH2Cl2 (1.1 mL, 1.1 mmol, 1 M) was added to a solution of N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (100 mg, 0.36 mmol) at 0° C. The reaction mixture was stirred overnight from 0° C. to room temperature and quenched with H2O. The solution was filtered through an Extrelut column, the column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was obtained without further purification. MS calculated for C15H19NO3+H: 262, observed: 262.