Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.[NH3:4].[C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[C:10]([CH3:16])[CH:9]=1)(=[O:7])[CH3:6].[O:17]1CCCC1>>[C:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:4])=[O:17])=[C:10]([CH3:16])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: C1CCOC1
Reactant: N
Reactant: CC(=O)c1ccc(CCl)c(C)c1
Solvent: ClCCl
Product: CC(=O)c1ccc(C(N)=O)c(C)c1
Reaction time: 2 h

Procedure:
21 ml of dichloromethane was added to 2 g of concentrated aqueous ammonia, and the mixture was cooled with ice. A dichloromethane (3 ml) solution of 1.39 g of crude 4-acetyl-2-methylbenzyl chloride was added slowly to the mixture, and stirred for 2 hours with ice cooling. 24 ml of tetrahydrofuran was added to the reaction solution, and further stirred for 2 hours at room temperature. Then, large part of the solvent was distilled off under reduced pressure, and the slurry-state reaction solution was filtered. The obtained solid was washed with water and toluene. The solid was dried under reduced pressure to obtain 1.03 g of 4-acetyl-2-methylbenzoic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C[O-].[Na+].Cl>COCCOC.O.CCOC(C)=O>[F:13][C:14]([F:21])([F:20])[C:15](=[O:16])[CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc(C(C)=O)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To stirred solution of 1-(3-chloro-4-methoxyphenyl)ethanone (2.2 g, 12 mmol) in DME was added ethyl trifluoroacetate (4.28 ml, 36 mmol) and sodium methoxide (4.25 g, 72 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. EtOAc (200 ml) and water (50 ml) were added, and the pH of the aqueous layer was adjusted to 6 by addition of 1 N HCl solution. The organic layer was washed with brine (50 ml), dried over MgSO4, and concentrated in vacuo to give the title compound in quantitative yield. This was used for the next coupling step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][S:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:16]=[C:17]([N:23]4[CH2:28][CH2:27][S:26][CH2:25][CH2:24]4)[CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1
Reactant: C1CSCCN1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(N2CCSCC2)n1

Procedure:
The title compound, MS: m/e=395.1, 397.1 (M+H+), was prepared in accordance with the general method of example 27 from 2-[4-(3-chloro-phenylethynyl)-2-methylimidazol-1-yl]-6-fluoro-pyridine and thiomorpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)/[C:24](=[CH:32]/[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)/[C:23]1=[O:40])=[O:21])[CH3:18].CO>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=2)[C:24]2([CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:23]1=[O:40])=[O:21])[CH3:18]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(Cl)c1
Temperature: 135 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (20 mL) was added E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in example 6b (0.3 g, 0.83 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 135° C. for 1 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-chloro-2′,4′-bis(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.45 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-methoxyphenylboronic acid according to the general procedure B. Obtained as an orange solid (818 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[F:30][C:31]1[CH:32]=[C:33]([C@@H:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][NH:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:37][C:35]1[CH:34]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][N:39]2[C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[CH:21]=2)=[O:28])[CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CC(C)(C)CCC4c4cc(F)cc(F)c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.16 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 70 mg (0.16 mmol) (S)-2-(3,5-difluorophenyl)-5,5-dimethylpiperidine in 0.04 mL (0.72 mmol) DIPEA and 0.80 mL DMF were combined with 65 mg (0.17 mmol) HATU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][NH:28][CH3:29]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](=[O:25])(=[O:24])[N:28]([CH3:29])[CH3:27]
Reactant: Nc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CNC
Product: CN(C)S(=O)(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C

Procedure:
A mixture of 5-amino-4-chlorosulphonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.2 g) and dimethylamine (17.6 ml of a 40% aqueous solution) was heated on a steambath for 1 hour, cooled, and poured onto crushed ice (50 g) to give a brown solid. This solid was filtered, dried, and recrystallized from toluene to give 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(N,N-dimethylsulphamoyl)-3-trifluoromethylpyrazole (0.8 g) as light brown crystals, m.p. 177.6°-178.6° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[C:27]([F:36])=[C:28]([C:32]2([NH2:35])[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:9]1[C:22](=[O:24])[NH:35][C:32]1([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[C:27]=2[F:36])[CH2:33][CH2:34]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Reactant: NC1(c2cccc(Cl)c2F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)NC1(c2cccc(Cl)c2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-3-(tert-butyl-dimethyl-silanyloxy)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 0.825 mmol), 1-(3-chloro-2-fluoro-phenyl)-cyclopropylamine (prepared as described in Part C, 272 mg, 0.908 mmol) and HBTU (376 mg, 0.99 mmol) in DMF (10 mL) was added DIPEA (0.432 ml, 2.476 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 h at 25° C. Then quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with EtOAc (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 531.5/533.5 [M+H]+, 505.5 [M+NH4]+, 510.4 [M+Na]+; tR (UPLC conditions m): 1.55 min.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:11][CH2:10][C:9](OC)=[N:8][CH2:7][CH2:6]1)([CH3:4])[CH3:3].[Cl-:14].[NH4+:15]>CCO>[ClH:14].[CH3:1][C:2]([CH:5]1[CH2:6][CH2:7][NH:8][C:9](=[NH:15])[CH2:10][CH2:11]1)([CH3:4])[CH3:3]
Reactant: COC1=NCCC(C(C)(C)C)CC1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CCO
Product: CC(C)(C)C1CCNC(=N)CC1
Product: Cl

Procedure:
The product of EXAMPLE 83 (2.5 g, 13.6 mmol) in 50 mL of EtOH was reacted with ammonium chloride (730 mg, 13.6 mmol) by the method of EXAMPLE 27 to yield 2.2 g (78%, of the title material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13]O)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:17])=O.N1C2C=CC=CC=2N=N1.[OH-].[Na+]>O.O1CCCC1.CN(C)C(=O)C>[Cl:17][CH2:13][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[O:12][N:11]=1
Reactant: Nc1ncccc1-c1cc(CO)no1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]nnc2c1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1ncccc1-c1cc(CCl)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of [5-(2-aminopyridin-3-yl)isoxazol-3-yl]methanol (0.19 g, 1 mmol) and N,N-dimethyl acetamide (1 mL) was added a mixture of thionyl chloride (0.15 mL, 2 mmol), benzotriazole (0.26 g, 2.2 mmol) and tetrahydrofuran (1 mL) under an ice cooling, which was stirred at room temperature for 30 minutes. To the reaction mixture were added water and 5N aqueous sodium hydroxide to adjust basic, then extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water. The solvent was evaporated under a reduced pressure to obtain the title compound (0.21 g) as a pale yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:30])([F:29])[CH:13]([OH:28])[CH2:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([S:25][CH3:26])[CH:23]=2)[O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[F:30][C:12]([F:11])([F:29])[C:13](=[O:28])[CH2:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([S:25][CH3:26])[CH:23]=2)[O:18][CH2:17][CH2:16]1
Reactant: CSc1ccc2c(c1)C(C)(CC(O)C(F)(F)F)CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CSc1ccc2c(c1)C(C)(CC(=O)C(F)(F)F)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a chilled (−60° C.) solution of 0.254 mL (2.9 mmol) of oxalyl chloride in 5 mL of methylene chloride was added a solution of 0.414 mL (7 mmol) of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of 450 mg (1.46 mmol) of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-ol in 2.5 mL of dichloromethane was added. The mixture stirred for 15 minuets and then 1.2 mL (8.7 mmol) of triethylamine was added. The reaction was warmed to room temperature for 30 minutes and then concentrated in vacuo. The residue was diluted with water and extracted with diethyl ether. The combined organic fractions were washed with four portions of water, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 340 mg (94%) of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-one as an oil.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](I)[CH2:24][CH3:25]>>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH2:23][CH2:24][CH3:25])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCI
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Product: CCCOC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 1-(4-benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine and n-propyl iodide. NMR of hydrochloride salt:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:40][CH2:41][N:42]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)=[CH:19][CH:20]=3)=[O:23])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=640.96 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1cccc(F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-fluoro-phenyl)-butan-2-one.
Reaction SMILES: S(O)(O)(=O)=[O:2].C(N1C[CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]C1)(=N)N.[OH-:22].[Na+]>C(O)C>[CH3:11][N:12]([CH:15]=[C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]1=[O:2])[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CCO
Product: CN(C)C=C1C(=O)CCCC1=O
Yield: 100 %

Procedure:
To an ethanol suspension (60 ml) of 10.73 g (40 mmol) of 1-amidino-4-benzylpiperazine sulfate, were added an ethanol solution (80 ml) of 1.6 g (40 mmol) of sodium hydroxide and then 6.69 g (40 mmol) of the 2-dimethylaminomethylenecyclohexane-1,3-dione obtained in Referential Example 46. The resultant mixture was heated under reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off. The residue was added with 100 ml of water and then extracted twice with 200 ml of ethyl acetate. The ethyl acetate layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Ethyl acetate was the distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 9.90 g of the intended product as light yellowish crystals (yield: 77%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:20](=[O:22])=[O:21]>C1COCC1.CCOCC>[F:13][C:10]1([F:14])[CH2:11][CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:20]([OH:22])=[O:21])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: O=C=O
Reactant: FC1(F)CC[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1ccc([C@@H]2CCC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.0 g (3.8 mmol) of (R)-3-(4-bromophenyl)-1,1-difluorocyclopentane (from Step B) in 15 mL of THF at −78° C. was treated with 1.6 mL (4.0 mmol) of 2.5M BuLi in hexanes. After stirring for 15 min, the reaction mixture was added to a suspension of dry ice in 200 mL of Et2O. The mixture was allowed to warm to rt. The reaction mixture was extracted with 100 mL of 1 N NaOH. After separating phases, the aqueous layer was acidified to pH 1-2 with concentrated HCl. The aqueous phase was extracted with 3×100 mL of CH2Cl2. The combined organic phases were dried and concentrated to give 0.67 g of the title compound: 1H NMR (CD3OD) δ 1.87 (m, 1H), 2.13-2.37 (m, 4H), 2.54 (m, 11H), 3.41 (m, 1H), 7.39 (d, J=8.2, 2H), 7.97 (d, J=8.2, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:53]1([NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCCC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclopentanamine (8.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.9 mg, 48%). LC-MS m/z 641 (M+H)+.
Reaction SMILES: [S:1]1[C:5]([SH:6])=[N:4][N:3]=[C:2]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[SH:6][C:5]1[S:1][C:2]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:3][N:4]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Sc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Sc1nnc(S)s1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 1,3,4-thiadiazole-2,5-dithiol (945 mg, 6.05 mmol), NaH (60% dispersion in mineral oil, 264 mg, 6.60 mmol), and 3-chloropyrazine-2-carbonitrile (840 mg, 6.00 mmol) in DMF and benzene (10 ml, 1/1) by stirring at 50° C. under nitrogen atmosphere for 4 hr.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.ClC(OCC(C)C)=O.C[Si](C)(C)[O:45][NH2:46]>ClCCl.CO>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[N:16]=2)[CH2:11][C:12]([NH:46][OH:45])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CO
Product: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-{3-[(propylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}hexanoic acid (Preparation 97) (298 mg, 0.77 mmol) and 2,6-lutidine (135 μl, 1.16 mmol) in dichloromethane (10 ml) was cooled to 0° C., treated with isobutyl chloroformate (100 μl, 0.77 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (310 μl, 2.31 mmol) was added and the mixture was stirred for 4 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol (5 ml) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with hydrochloric acid (1 M) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford the title compound as a white solid (140 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.O>CN(C=O)C>[Cl:3][C:4]1[N:5]=[C:6]([Cl:13])[C:7]2[CH:12]=[CH:11][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:8]=2[N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of NaH (119 mg, 60% in oil, 2.98 mmol) in DMF (5 mL) was added 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 2.13 mmol) at 0° C. The resulting mixture was stirred for 30 min before 2-(trimethylsilyl)ethoxymethyl chloride (0.42 mL, 1.1 eq) was added. The mixture was then warmed up to room temperature and stirred for 1 hr. Water was added to quench the reaction. Extraction with CH2Cl2 followed by drying combined organic layers, evaporation, and chromatography on silica gel (20% EtOAc in heptane as eluent) gave the desired product in 84% yield (570 mg).