Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2cc(F)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2cc(F)ccc12

Procedure:
Ethyl 2-[6-fluoro-1-(4-nitrobenzyl)-1H-indazol-3-yl]acetate (357 mg, 1.0 mmol) was dissolved in methanol (20 mL). 10% Pd/C (15 mg) was added, and reacted under hydrogen atmosphere for half an hour. TLC (petroleum ether:ethyl acetate=2:1) indicated that starting material disappeared. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and the resulting solid was used for the next step directly.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](F)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:10]=1>>[NH2:8][C:9]1[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([S:24](=[O:26])(=[O:25])[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:22][CH:23]=2)[N:10]=1
Reactant: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Reactant: CN(C)CCCN
Product: CN(C)CCCNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
3-Dimethylaminopropylamine (3 ml) was added to 4-amino-5-cyano-2-(4-fluorosulphonylanilino)pyrimidine (Method 1; 250 mg, 0.853 mmol), the mixture was heated at 90° C. for 45 minutes then stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane/methanol (50:50:0) increasing in polarity to (80:0:20). The product was triturated with ether and a few drops of methanol and the resulting solid collected by filtration to give the title compound (176 mg, 55%). NMR: 1.45 (t, 2H), 2.04 (s, 6H), 2.10 (t, 2H), 2.72 (t, 2H), 7.60 (s, 2H), 7.62 (d, 2H), 7.98 (d, 2H), 8.40 (s, 1H); m/z 376 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=C(CN1CCN(c2cccc(Br)c2)CC1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(CN1CCN(c2cccc(-c3ccccc3)c2)CC1)N1CCN(C2CCC2)CC1
Temperature: 85 °C

Procedure:
In a sealed vial, dissolve 1-(3-bromophenyl)-4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazine (17 mg, 0.04 mmol), phenyl boronic acid (9.8 mg, 0.08 mmol), and Pd(PPh3)4 (2.3 mg, 0.002 mmol) in dioxane (0.7 mL) and 2N K2CO3 (0.1 mL). Degas with N2 and seal the vial. Heat the mixture at 85° C. overnight. Cool and add partition EtOAc (0.5 mL) and 1N NaOH (0.5 mL). Extract the organic phase and place directly on SCX ion exchange resin. Wash the resin with EtOAc/MeOH (9:1). Discard this wash. Wash the resin with EtOAc/MeOH/TEA(9:1:1) and collect. Remove the solvent to yield the title compound. 1H NMR (CDCl3) δ 7.59-7.56 (m, 2H) 7.45-7.40 (m, 2H), 7.36-7.31 (m, 2H), 7.13-7.07 (m, 2H) 6.94-6.90 (m, 1H), 3.64 (t, 4H), 3.29-3.25 (m, 6H), 2.73-2.67 (m, 5H), 2.33-2.27 (m, 4H), 2.06-2.02 (m, 2H), 1.90-1.83 (m, 2H), 1.75-1.69 (m, 2H); LC-MS (M+1) 419.06.
Reaction SMILES: S1C=CC=C1CC(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][N:33]=[C:34]=[O:35].[F:36][C:37]1[C:38](=[O:44])[NH:39][C:40](=[O:43])[NH:41][CH:42]=1>C1C=CC=CC=1.C(N(CC)CC)C>[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH:33][C:34]([N:41]1[CH:42]=[C:37]([F:36])[C:38](=[O:44])[NH:39][C:40]1=[O:43])=[O:35]
Reactant: O=C=NCc1cccs1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C(O)Cc1cccs1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1cccs1)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 2-thienylacetic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-thienylmethyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(2-thienylmethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 13.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:21][CH2:20]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[OH:29])=[O:7])=[CH:4][CH:3]=1.[C:32](N1C=CN=C1)([N:34]1C=CN=[CH:35]1)=[O:33].CN.O>C1COCC1.C(OC)(C)(C)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:28][O:27][CH2:26]5)[CH2:23][CH2:24]4)[CH:17]=3)[O:12][CH2:11][C@@H:10]2[O:29][C:32](=[O:33])[NH:34][CH3:35])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(N[C@H]1c2cc(N3CCN(C4COC4)CC3)ccc2OC[C@@H]1O)c1ccc(F)cc1
Agent: CN
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)O[C@H]1COc2ccc(N3CCN(C4COC4)CC3)cc2[C@@H]1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-fluoro-N-[(3R,4S)-3-hydroxy-6-[4-(oxetan-3-yl)piperazin-1-yl]chroman-4-yl]benzamide (72.0 g, 168 mmol) in THF (648 mL) add 1,1′-carbonyldiimidazole (35.5 g, 219 mmol) and stir the solution at room temperature overnight. Cool the mixture to 5° C. and add a solution of 2 M methylamine in THF (210 mL, 421 mmol, 2.5 eq) dropwise over a period of 15 min. Stir for 30 min. and pour over a mixture of water (720 mL) and methyl tert-butyl ether (216 mL). Stir the mixture for 30 min. and decant the phases. Extract the aqueous phase with dichloromethane (3×216 mL). Wash the combined organic phases with brine (3×100 mL), dry over anhydrous sodium sulfate, and concentrate in vacuo. Suspend the residue in ethyl acetate (720 mL), heat at reflux for 2 hr. and cool to 10° C. Collect the solid by filtration and dry under vacuum overnight to obtain the title compound (64.0 g, 78%) as a white solid. LC-ES/MS m/z 485 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([CH2:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C>[NH2:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: Cc1cccc(CC(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(CC(=O)NC(C)C)c1N

Procedure:
To 3-methyl-N-(1-methylethyl)-2-nitrobenzeneacetamide (i.e. the title product of Step A) (0.40 g, 1.7 mmol) and 10% palladium on carbon (0.13 g) was added 20 mL of ethanol. The reaction mixture was placed under a balloon of nitrogen overnight. Then the reaction mixture was filtered through Celite® diatomaceous filter aid. The solvent was removed with a rotary evaporator to afford the title compound as a tan solid (0.29 g).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:42])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34]CC4C=CC=CC=4)[C@@H:22]([O:23]CC4C=CC=CC=4)[C@@H:13]3[O:14]CC3C=CC=CC=3)[C:6]=2[N:7]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[NH:3][C:4](=[O:42])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][OH:34])[C@@H:22]([OH:23])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c(=O)[nH]1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: -40 °C

Procedure:
Compound 39 is dissolved in dry dichloromethane and deprotected using an excess of boron trichloride (1M in dichloromethane) at -78° C. and allowed to warm to -40° C. for 2 hours before quenching with methanol. The residue after workup is crystallized from water to yield 40 as a colorless crystalline solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][OH:9])[CH3:2]
Reactant: CCOCOc1c(C)cccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOCOc1c(C)cccc1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a stirred solution of 2-(ethoxymethoxy)-3-methylbenzaldehyde (2.0 g, 10.3 mmol) in methanol (25 mL) was added sodium borohydride (0.42 g, 11.1 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min. The solvent was then removed and the residue was purified by flash column chromatography (hexanes/ethyl acetate=4:1, v/v) to provide the title compound (2.02 g, 100%) as a colorless oil.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]3[O:13][CH2:12][O:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3]1.C(O)(=O)C.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:12]1[O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH2:2]3)=[CH:6][C:7]=2[O:13]1
Reactant: OC1CCc2cc3c(cc21)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: C1=Cc2cc3c(cc2C1)OCO3
Yield: 92.7 %

Procedure:
A solution of 10.8 g of 1-hydroxy-5,6-methylenedioxyindane and 15 ml of acetic acid in 100 ml of toluene was heated under reflux for 4 h. Water and a small amount of potassium carbonate were added to the reaction mixture. After extraction with ethyl acetate, the organic layer was washed with water and an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the residue was treated according to silica gel column chromatography (chloroform/hexane=1:3) to obtain 9.0 g of the intended compound in the form of colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Agent: Cl
Product: O[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, MS: m/e=294.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and trans-4-aminocyclohexanol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:25][CH2:24]2)=[CH:4][C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8].C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl.O>[CH2:21]([O:20][C:5]1[C:6]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:19][C:2]([NH:1][C:50]([C:46]2[O:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:27][CH2:28]2)[CH:4]=1)[CH3:22]
Reactant: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(N)cc1C(=O)NCCCN1CCCC1=O
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)cc1C(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 5-amino-2-ethoxy-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide 8c (44.8 mg, 0.09 mmol, 100 mol %) and N,N-diisopropylethylamine (0.05 ml, 0.28 mmol, 300 mol %) in dichloromethane (2.0 ml) was added furan-2-carbonyl chloride (0.01 ml, 0.11 mmol, 120 mol %) and a catalytic amount of N,N-dimethylaminopyridine. The reaction was stirred for 16 h at room temperature and then diluted with water and extracted three times with dichloromethane. The combined organics were dried over sodium sulfate and concentrated and the residue was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford furan-2-carboxylic acid [4-ethoxy-5-[3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 8g (30.7 mg, 0.05 mmol, 53.6%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([N+:24]([O-])=O)[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:27][CH3:28])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3]>CO.[Pd]>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH2:24])[C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:27][CH3:28])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c([N+](=O)[O-])cnc32)cc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)c(N)cnc32)cc1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A suspension of 2-[4-(2-ethyl-7-methyl-6-nitro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 3, 2.5 g, 6.6 mmol), 10% Pd—C (250 mg, 0.23 mmol) in methanol (100 mL) was stirred under hydrogen atmosphere for 2 h. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 2.4 g (99%) of the title compound as a brown oil: 1H-NMR (CDCl3) δ 7.82 (1H, s), 7.41 (2H, d, J=8.2 Hz), 7.32 (2H, d, J=8.4 Hz), 4.35 (2H, t, J=7.0 Hz), 3.51 (2H, br.s), 3.03 (2H, t, J=7.0 Hz), 2.82 (2H, q, J=7.5 Hz), 2.53 (3H, s), 2.35 (2H, q, J=7.5 Hz), 1.29 (3H, t, J=7.5 Hz), 1.44 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cccc(F)c1
Temperature: 80 °C
Yield: 54 %

Procedure:
To a solution of ethyl 2-(3-fluorophenyl)acetate (I8) (10.1 g, 55.0 mmol) in CCl4 (250 mL), NBS (9.70 g, 55.0 mmol) is added and the mixture refluxed for 2 hours at 80° C. (LC-MS monitoring: complete conversion). The solvent is evaporated and the resulting crude is dissolved in DCM and purified by filtration on a silica bed in order to obtain 7.80 g of (I9) as a colorless oil (54% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13]Br>>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccncc1
Reactant: Clc1ccc(CCBr)c(Cl)c1
Product: CC(CCc1ccc(Cl)cc1Cl)c1ccncc1
Yield: 25.6 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 2,4-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.67 g of the desired compound (yield: 25.6%). The resulting compound was identified as 1-(2,4-dichlorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 9) by the following analytical results.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14][CH3:15])[CH3:8]>O.C(O)C>[CH2:7]([O:9][CH2:10][N:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:12](=[O:16])[CH2:13][S:14]([CH3:15])=[O:2])[CH3:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOCN(C(=O)CSC)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCN(C(=O)CS(C)=O)c1cccc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
A solution of sodium periodate (20.5 g) in water (190 ml) was added dropwise to a stirred solution of crude product of Step 2 in ethanol (850 ml) at 5° C. The mixture was allowed to reach 20° C. gradually and stirred for 24 hours, then concentrated under reduced pressure. The concentrate was extracted with dichloromethane (500 ml), the extract dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product as a brown oil (27.5 g). 1H NMR (CDCl3l ): δ 1.24(3 H,t); 2.76(3 H,s); 3.56(2 H,s); 3.67(2 H, 5.12(2 H,s); 7.51-7.69(4 H,m).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][OH:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=[O:22])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CO)ccc2[nH]1)c1c(F)cccc1F
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 47.7 %

Procedure:
A mixture of 2,6-difluoro-N-[3-(5-hydroxymethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (800 mg, 2.17 mmol) and MnO2 (5.00 g, 57.5 mmol) in CH2Cl2/MeOH (10:1, 110 ml) was stirred at ambient temperature for 5 days. The mixture was filtered through a plug of Celite washing with MeOH and the filtrate reduced in vacuo to give 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (380 mg, 48%) as a yellow solid. (LC/MS: Rt 3.41, [M+H]+ 368.04).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH:13]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[N:22]=2)=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH:3][C:4]3[CH:5]=[CH:6][C:7]4[S:11][C:10]([CH3:12])=[N:9][C:8]=4[CH:13]=3)=[O:26])=[C:23]([CH3:30])[N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Reactant: Cc1nc2cc(N)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2cc(NC(=O)c3ccc(-c4ccc(F)cc4)nc3C)ccc2s1

Procedure:
5-Amino-2-methylbenzothiazole dihydrochloride (98 mg, 0.41 mmol), 6-(4-fluorophenyl)-2-methylnicotinic acid (D3) (96 mg, 0.42 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol) and 4-dimethylaminopyridine (25 mg, 0.21 mmol) in DCM (2 ml) were stirred at room temperature overnight. The reaction mixture was purified directly by column chromatography, eluting with a 0-10% MeOH/DCM gradient to give the title compound as a white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 8.42 (d, 1H), 8.21 (dd, 2H), 8.02 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.34 (t, 2H), 2.80 (s, 3H), 2.67 (s, 3H). MS(ES): MH+ 378, M−H+ 376.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO)N2
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
To a solution of (2R,5S,7R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 18, 80 mg, 0.136 mmol) in Dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (84 mg) that was used in the next step without further purifications. LC/MS (Basic gradient conditions): Rt=4.205 min, m/z 662 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2([CH3:32])[CH2:17][CH2:16][C:15]3[C:18]([CH3:31])=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)=[S:11])[CH:3]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2([CH3:32])[CH2:17][CH2:16][C:15]3[C:18]([CH3:31])=[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([CH3:23])=[C:21]([CH3:22])[C:14]=3[O:13]2)=[S:11])[CH:3]=1
Reactant: CCOC(=O)COc1c(C)c(C)c2c(c1C)CCC(C)(C(=S)Nc1cc(C)cc(C)n1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)nc(NC(=S)C2(C)CCc3c(C)c(OCC(=O)O)c(C)c(C)c3O2)c1
Reaction time: 2 h

Procedure:
1.77 grams (4 mmol) of the compound of Example 67 are dissolved in 40 cm3 of ethanol. 4 cm3 of 2N sodium hydroxide are added dropwise. The mixture is stirred for 2 hours, then the reaction mixture is diluted with 60 cm3 of water and acidified with acetic acid. The mixture is filtered, washed with water and then dried to obtain the title product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 71.6 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.3 g, 11 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 52a, AgF (0.7 g, 5.5 mmol), and triethylamine (2.9 g, 29 mmol) in dichloromethane (200 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (3 g, 64%).