Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:7]=[C:2]([Br:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]2=[O:8])=[CH:19][CH:18]=1
Reactant: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(Br)c(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of 5-bromo-4-methyl-3-nitro-2-pyridone (0.60 g, 2.5 mmol) in DMF (15 mL) was added sodium hydride (60% suspension in oil, 0.103 g). After 30 minutes, 4-methoxybenzyl chloride (0.35 mL) was added, and the mixture was stirred overnight at rt. Ethyl acetate was added and the organic phase was washed with water, dried (Na2SO4), filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/1)) gave 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-nitro-2-pyridone (0.60 g, 1.7 mmol, 68%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:23]=[N:24][C:25]4[N:26]([C:32](=[O:34])[NH2:33])[CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=3)[C:19]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:36](F)(F)C(O)=O>C(Cl)Cl>[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:31]=[C:30]4[C:25](=[N:24][CH:23]=3)[N:26]([C:32]([NH2:33])=[O:34])[CH2:27][CH2:28][CH2:29]4)[C:19]=2[C:20]#[N:21])[CH2:12][CH2:13]1)(=[O:5])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Reaction time: 16 h

Procedure:
The crude 5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-4-cyano-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.22 mmol) is dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 16 hrs and all the solvent is removed in vacuo. The residue is dissolved in MeOH and is passed through StratoSpheres SPE PL-HCO3 cartridge. The solution is concentrated to give the crude 6-(4-cyano-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide which is used without purification.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3]Br.[SH:11][C:12]1[NH:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C)C=O>[C:5]1([CH:2]2[S:11][C:12]3=[N:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[N:13]3[CH2:3]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCC(Br)c1ccccc1
Reactant: Sc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: c1ccc(C2Cn3c(nc4ccccc43)S2)cc1
Temperature: 100 °C

Procedure:
(1,2-Dibromoethyl)benzene (21 g) was treated with 2-mercaptobenzimidazole (17 g) in dimethylformamide (100 ml) and the mixture was heated at 100° C. for 36 hours. On cooling, the solid material was removed by filtration and recrystallised from methanol and ethyl acetate to give the title compound as the hydrobromide salt (13.68 g). mp 207°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24](O)=[O:25])[NH:13][C:12]43[CH2:29][C:28]([CH2:32][F:33])([CH2:30][F:31])[CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([N:44]([CH3:46])[CH3:45])=[O:43])[CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([NH:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([C:42](=[O:43])[N:44]([CH3:45])[CH3:46])[CH2:40][CH2:41]4)=[O:25])[NH:13][C:12]43[CH2:27][C:28]([CH2:30][F:31])([CH2:32][F:33])[CH2:29]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1NC2(CC(CF)(CF)C2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CN(C)C(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)[C@@H]2NC3(CC(CF)(CF)C3)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)CC1

Procedure:
The compound (70 mg, 0.14 mmol) obtained in Step 1 of Example 121 and trans-4-amino-N,N-dimethylcyclohexanecarboxamide hydrochloride (WO2008/068171) (29 mg, 0.17 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 62 mg (68%) of the title compound as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:29][CH:28]([OH:30])[CH:27]([OH:31])[C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:20]1[CH2:29][CH:28]([OH:30])[CH:27]([OH:31])[C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccccc1C1(N2CC(O)C(O)[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CC(O)C(O)[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 52.7 %

Procedure:
With 300 mg of the compound obtained in Step 19-7 and 215 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 248 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[CH3:25][C:26]([N+:30]([O-:32])=[O:31])([CH3:29])[CH2:27][OH:28].C(N(CC)CC)C>CC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:28][CH2:27][C:26]([CH3:29])([N+:30]([O-:32])=[O:31])[CH3:25])=[O:11]
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.8 g, 0.01 mole) in acetone (10 ml) was added 2-methyl-2-nitropropanol (1.19 g, 0.01 mole) in acetone (10 ml) followed by triethylamine (1.01 g, 0.01 mole) in acetone (5 ml). The temperature rose and a white precipitate formed. The reaction was heated to reflux for 2.5 hours and then stirred overnight at room temperature. After dilution with water (75 ml), the solution was extracted twice with methylene chloride (25 ml @). The organic solution was then washed with 5% sodium hydroxide and finally with a brine solution. The dried solution was concentrated to give an amber oil 2.83 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH2:31]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[CH2:32][CH3:33]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:35]4[C@H:34]([CH2:31][CH2:32][CH3:33])[CH2:38][O:37][C:36]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CCC[C@@H]1COC(=O)N1
Product: CCC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(N2CCCS2(=O)=O)c1
Yield: 69.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and (R)-4-propyloxazolidin-2-one (64.58 mg) described in Preparation Example 29, the title compound (188.8 mg) was obtained.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([CH2:9][C:10](=O)[CH3:11])=[O:8])=[CH:5][N:4]=1.[ClH:15].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[ClH:18].[CH3:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]([OH:8])[CH2:9][CH:10]([Cl:15])[CH3:11])=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)CC(C)Cl)cn1

Procedure:
A suspension of the sodium salt of 6-methyl-nicotinoyl-acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted with thionyl chloride in a known manner. Reduction of the reaction product gives 1-(2-methyl-5-pyridyl)-3-chloro-butan-1-ol hydrochloride which is used without additional purification
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:10]3([CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)[CH:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:10]3([CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCC2(C=C(c3ccc(C)cc3)c3ccccc3O2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCC2(CC1)CC(c1ccc(C)cc1)c1ccccc1O2
Temperature: 40 °C

Procedure:
To a solution of ethyl 4-(4-methylphenyl)spiro[2H-1-benzopyran-2,4′-piperidine]-1′-acetate (730 mg, 0.194 mmol) in ethyl alcohol (125 cm3) was added 10% is palladium on carbon. This mixture was heated to 40° C. for 7 h under an atmosphere of hydrogen (4 bar) and then it was filtered whilst still warm and the filter cake was washed with hot ethyl alcohol (3×50 cm3). The solvent was removed in vacuo and the resulting compound Was recrystallised from ethyl alcohol (67%). This ester was hydrolysed according to the procedure in Example 1; m.p. 247-249 ° C.; (M+H)+=352.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3ccncc3)cnn12
Yield: 23 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (94 mg, 46%). MS (ISP) 409.2 [(M+H)+]; mp 260° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3o2)CC1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (390 mg), 4-(methanesulfonyl)phenyl boronic acid (350 mg), 2 M aqueous Na2CO3 solution (1.50 mL), and 1,4-dioxane (10 mL) is sparged with Ar for 10 min. Pd(PPh3)4 (100 mg) is added and the resulting mixture is stirred at 170° C. for 1 h in a microwave oven. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40→40:60) to give the title compound. LC (method 2): tR=1.23 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=1.[CH3:18][NH2:19]>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[N:3]=[C:2]([NH:19][CH3:18])[N:7]=1
Reactant: Clc1nc(Cl)nc(N2CCc3ccccc32)n1
Reactant: CN
Solvent: ClCCl
Product: CNc1nc(Cl)nc(N2CCc3ccccc32)n1
Yield: 82 %

Procedure:
To a mixture of 2,4-dichloro-6-indolin-1-yl-1,3,5-triazine (30 g, 112 mM) and methylene chloride (300 ml) at 0° C. was added a 33% solution of methylamine (30 ml) in IMS. The mixture was allowed to attain ambient temperature. After two days the mixture was washed with water. The methylene chloride layer was separated, dried (MgSO4), and the solvent evaporated. The resultant solid was recrystallised from toluene: ethanol (70:30). There was thus obtained 2-chloro-4-indolin-1-yl-6-methylamino-1,3,5-triazine (24 g, 82% yield). m.p 239°-240° C.; NMR: DMSOd6 : 2.75-2.95 (3H, complex, rotamers, NHMe), 3.05-3.2 (2H,t,CH2 --CH2N--), 4.0-4.2(2H,q,CH2CH2N) (rotamers), 6.9-7.3(3H, complex, aromatic), 7.9-8.1 (1H, broad, aromatic), 8.1-8.4(1H, broad, NH).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([OH:11])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[CH3:22][C:23]([CH3:27])([CH3:26])[CH2:24]O>>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH2:22][C:23]([CH3:27])([CH3:26])[CH3:24])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2O)cc1
Reactant: CC(C)(C)CO
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OCC(C)(C)C)cc1

Procedure:
The intermediate, 2-(2,2,2-trifluoroethyl)-4-hydroxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone prepared in Example 90C was reacted with 2,2-dimethylpropanol to provide 2-(2,2,2-trifluoroethyl)-4-(2,2-dimethylpropoxy)-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone according to the method of Example 90D.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:19])[CH2:16][CH:17]=[CH2:18])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CN=C1.[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([Si:29]([CH3:32])([CH3:31])[O:19][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)[CH2:16][CH:17]=[CH2:18])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCC(O)c1ccc(CCCCCCCC)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC(O[Si](C)(C)C(C)(C)C)c1ccc(CCCCCCCC)cc1
Reaction time: 72 h
Yield: 115.4 %

Procedure:
1-(4-octylphenyl)but-3-en-1-ol (11.5 g, 44.2 mmol) and imidazole (3.16 g, 46.4 mmol) were combined in DMF (221 ml). Tert-butyldimethylchlorosilane (6.66 g, 44.2 mmol) was added and the reaction stirred for about 72 h. The reaction was quenched by addition of water and ethyl acetate (500 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined ethyl acetate extracts were washed with 5% LiCl solution (3×). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to provide tert-butyldimethyl(1-(4-octylphenyl)but-3-enyloxy)silane (19.108 g, 51.0 mmol, 115% yield) as a colorless oil. LC/MS (method f) Rt=5.32, 3.89 min.; MS m/z: 243.21 (M-OTBDMS)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:8])=[CH:5][N:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH:36][CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]=2)[CH2:32][CH2:31]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Product: CN1CCC(NCc2ccc(C(N)=O)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-methylpiperidin-4-amine (0.4 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-((1-methylpiperidin-4-ylamino)-methyl)nicotinamide. MS (Q1) 512.3 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.[C:11]([S-:16])(=[S:15])OCC.[K+].Cl>CN(C=O)C>[SH:16][C:11]1[S:15][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(S)sc2c1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 4-amino-3-chlorobenzonitrile (12.2 g, 80.2 mmol) from Step 1 of this Example in DMF (60 mL) was added potassium O-ethyl carbonodithioate (28.9 g, 180.7 mmol) at rt. The mixture was refluxed for 4 h. After cooling to rt, the reaction mixture was poured into ice water and acidified with 2N aq HCl. The tan solids were collected and dried in vacuum oven overnight. Then the solids were refluxed with 500 mL of CHCl3 for 10 min. After cooling to rt, the mixture was treated with 200 mL of hexanes and sonicated for 20 min. The pale brown solid was collected by filtration to give 2-mercaptobenzo[d]thiazole-6-carbonitrile (12.9 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 14.16 (br s, 1H), 8.23 (d, J=0.9 Hz, 1H), 7.83 (dd, J=1.3, 8.5 Hz, 1H), 7.31-7.51 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.071 mmol), glycine (2.85 g, 38 mmol) and NaOMe solution (57 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-80% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound MS: (+) m/z 521.17 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].[CH3:20][C:21]1([CH3:29])[O:25][C@H:24]([C@H:26]([OH:28])[CH3:27])[CH2:23][O:22]1>O1CCCC1.CC1CCCO1>[Cl:8][C:6]1[CH:7]=[C:2]([O:28][C@@H:26]([C@@H:24]2[CH2:23][O:22][C:21]([CH3:29])([CH3:20])[O:25]2)[CH3:27])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:5]=1
Reactant: Fc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2ccc(F)cc2)n1)[C@@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
The sub-title product of step (ii) (85.7 g) and 60% sodium hydride (14.2 g) were suspended in tetrahydrofuran (1000 mL) and cooled in ice/water for 30 minutes. A solution of (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (Intermediate A) in 2-methyltetrahydrofuran (53% w/v) (104 mL) was added dropwise over 20 minutes and the reaction was stirred at 0° C. to room temperature for 20 hours. The reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The aqueous was re-extracted with ethyl acetate (2×500 mL) and the combined organics were dried and evaporated in vacuo. The crude material was purified by flash silica chromatography with gradient elution 0-30% ethyl acetate in isohexane using Isolera LS. Pure fractions were evaporated to dryness to afford to afford the sub-title product (94 g) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:33][C:30]2[CH:31]=[CH:32][C:27]([N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[CH:28][C:29]=2[N:34]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (214 mg, 0.777 mmol) and 4-morpholinobenzene-1,2-diamine (150 mg, 0.777 mmol) were dissolved in dry THF (10 mL), and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, DMSO-d6): δ 9.49 (d, 1H, J=2.0 Hz), 8.41 (dd, 1H, J=2.0 and 9.2 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.71 (m, 1H), 7.12 (m, 2H), 6.05 (dd, 1H, J=2.4 and 9.2 Hz), 4.75 (dd, 1H, J=2.4 and 6.8 Hz), 4.05 (m, 1H), 3.89 (m, 4H), 3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.22 (m, 4H), 2.21 (m, 2H), 1.87 (m, 1H), 1.73 (m, 1H).