Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:14]([NH:17][CH3:18])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CS(C)=O.O>[C:1]([S:14]([N:17]([CH2:23][CH:22]=[CH2:21])[CH3:18])(=[O:15])=[O:16])([C:4]([C:7]([C:10]([F:13])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=CCN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A 250 mL three-neck round-bottom flask equipped with thermometer, magnetic stirring, and addition funnel was charged with a solution of 75 g of C4F9SO2NHCH3 in 80 g of dimethyl sulfoxide. The solution was stirred while a solution of 17.1 g potassium hydroxide in 20 g of water was added in 2 mL aliquots via pipette. The solution turned cloudy during the addition, then cleared with additional stirring. Allyl bromide (31.9 g) was charged to the addition funnel, and added dropwise to the reaction mixture. A rise in temperature of the reaction mixture to 75° C. was noted during the addition. The reaction mixture turned cloudy shortly after the addition was begun, and stirring was continued overnight at room temperature. The reaction mixture was poured into a separatory funnel and allowed to stand until the liquid layers had separated. A few mL water were added to the mixture to facilitate phase separation. The lower layer was drawn off, washed with water and brine, and dried over anhydrous magnesium sulfate, leaving 76.0 g of a clear, colorless crude liquid product which was vacuum distilled to yield 68.7 g C4F9SO2N(CH3)CH2CH═CH2, b.p. 97-101° C. at 19 torr (2.5 kPa).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[O:18][CH2:19][CH3:20])(=O)=O.[I-:23].[Na+].CCOC(C)=O>CS(C)=O>[CH2:19]([O:18][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[I:23])[CH:16]=[O:17])[CH3:20]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1I
Temperature: 6.5 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-ethoxy-4-formyl-6-nitrophenyl trifluoromethanesulfonate (4.7 g, 13.7 mmol) in DMSO (10 mL) was added sodium iodide (6.2 g, 41.1 mmol). The mixture was stirred under N2 atmosphere at 3-10° C. overnight. EtOAc/aqueous workup. Purified by silica gel column chromatography (PE:EtOAc=50:1 to PE:EtOAc=10:1) (4.0 g, yield 91%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]#[N:16])=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH2:16])=[C:10]([O:17][CH3:18])[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1C#N
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CN
Yield: 68.9 %

Procedure:
A clear solution of tert-butyl(5-cyano-6-methoxy-4-methylpyridin-2-yl)carbamate (0.60 g, 2.279 mmol) in HOAc (5 mL) and ethanol (20 mL) was treated on an H-Cube apparatus (50 psi, 40° C., 1 mL/min., Raney Nickel cartridge) for 18 hr. LCMS showed that the reaction was complete (86% pure). The reaction was evaporated to dryness under vacuum. Purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 12% (5% NH4OH/MeOH) in CH2Cl2). The pure fractions were combined and evaporated to dryness under vacuum to give the product tert-butyl(5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.42 g, 1.571 mmol, 68.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.16 (s, 1H), 3.80 (s, 3H), 3.57 (s, 2H), 2.28 (s, 3H), 1.46 (s, 9H). MS(ES)+m/e 268.1 [M+H]+.
Reaction SMILES: C([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([F:18])[CH:12]=2)[C:6]([O:19][C@@H:20]2[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]2[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:5]1)(=O)C.C(=O)(O)[O-].[K+].C(O)(=O)C>CO>[F:18][C:13]1[CH:12]=[C:11]([CH2:10][C:7]2[C:6]([O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])=[N:5][NH:4][C:8]=2[CH3:9])[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccc(C)c(F)c2)c1C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(Cc2c(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)n[nH]c2C)cc1F
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 1-acetyl-4-[(3-fluoro-4-methylphenyl)-methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.75 g) in methanol (5 mL) was added potassium bicarbonate (0.030 g) under stirring at room temperature. The mixture was stirred at 50° C. for 3 hours. To the mixture was added glacial acetic acid (0.022 g) at 60° C., and the resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/5) to give 4-[(3-fluoro-4-methylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.610 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.O>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 82.4 %

Procedure:
To a stirred mixture of 2-amino-5-chloro-3-nitrobenzotrifluoride (250 mg, 1.043 mmol) in ethanol (4 mL) was added SnCl2.2 H2O (1.174 g, 5.217 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 and extracted with ethyl acetate. The extract was dried (Mg2SO4) and evaporated to give 181 mg (83%) of 2,3-diamino-5-chlorobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ 3.515 (s, 2H); 3.878 (s, 2H); 6.845 (s, 1H); 6.988 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:19])[CH3:2].C=O.[C:23](=O)([O-])O.[Na+]>C(O)=O>[CH2:1]([C:3]1([CH3:20])[N:15]([CH3:23])[C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]2=[O:12])[CH:4]1[CH3:19])[CH3:2]
Reactant: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CCC1(C)CC2(NC(=O)N(C)C2=O)C(C)C(C)(CC)N1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5.5 g of the 7,9-diethyl-3,6,7,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 2) obtained in Example 2 were added 1.8 g of formic acid and 6.3 g of 37% formalin; the mixture was stirred at room temperature for one hour and then refluxed by heating for 5 hours. After cooling the reaction mixture, its pH was adjusted to a value of 8 by addition of a 5% aqueous solution of sodium hydrogen carbonate; the solution was then extracted with ethyl acetate. The extract was dried over potassium carbonate and the solvent was then removed. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give 5.58 g of Compound 64, mp 190° - 195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[CH3:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[C:20](OS(C(F)(F)F)(=O)=O)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:20]1[C:19]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]2[CH3:12])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=2)[N:21]=1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (2,4-difluorophenyl)boronic acid (218.9 mg, 1.39 mmol) in dioxane (5.0 mL) and water (3 drops) was added (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, 0.69 mmol), K3PO4 (293 mg, 1.38 mmol) and Pd(PPh3)4 (39.97 mg, 0.03 mmol) with stirring for 1 hour at 95° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (192.0 mg, 70%)
Reaction SMILES: NC(CCC)C#N.[NH2:8][C@H:9]([C:17]([NH2:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:11]1([CH2:10][C@H:9]([NH2:8])[CH2:17][NH2:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCCC(N)C#N
Agent: [Al+3]
Agent: [H-]
Product: NC[C@@H](N)Cc1ccccc1
Yield: 35 %

Procedure:
Following the procedure as described in Preparation 11, making variations as required to replace 2-aminopentanenitrile with L-phenylalanineamide to react with lithium aluminum hydride, (S)-3-phenylpropane-1,2-diamine was obtained as a colorless solid in 35% yield: MS (ES+) m/z 151.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:16]=[O:17]>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH3:14])=[C:16]=[O:17]
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: Cc1c(N=C=O)ccc(C#N)c1C(F)(F)F

Procedure:
The title compound was prepared from 18D in a manner similar to that described in Experiment 2E.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[5,4-d]pyrimidin-7-yl)morpholine 14 (1.75 g, 6.85 mmol) in dry THF at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 uL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[5,4-d]pyrimidine-2-carbaldehyde 44.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:41](=[O:42])[CH2:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1cccc(CC(=O)N2C[C@@H]3[C@H](C2)C(c2ccccc2)(c2ccccc2)CC[C@@]3(O)c2ccccc2OC)c1
Yield: 58.5 %

Procedure:
By working in accordance with Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.28 g of (3-methoxyphenyl)acetic acid, 0.54 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(3-methoxyphenyl)acetyl]perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=2)(=[O:28])=[O:27])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: O=C(c1ccncc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 130 mg of 4-Trifluoromethoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.23 (d, 2H, J=8.0 Hz), 7.45 (m, 3H), 7.71 (m, 2H), 7.85 (d, 2H, J=8.8 Hz), 8.85 (d, 2H, J=6.4 Hz), 10.23 (s, 1H). MS: m/z 502.9 (M++1).
Reaction SMILES: [Cl:1]C1C=C(C=C(OC2C=C(O)C=CC=2Cl)C=1)C#N.ClC1C=C(C=C(OC2C=C(O[CH2:36][C:37]3[N:41]([CH3:42])[C:40]4[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=4[N:38]=3)C=CC=2Cl)C=1)C#N>>[Cl:1][CH2:36][C:37]1[N:41]([CH3:42])[C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[N:38]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(O)ccc2Cl)c1
Reactant: Cn1c(COc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)nc2ccccc21
Product: Cn1c(CCl)nc2ccccc21

Procedure:
In a manner similar to that described in Example 1 above for the synthesis of 1-2, from 50 mg (0.18 mmol) of 3-chloro-5-(2-chloro-5-hydroxyphenoxy)benzonitrile (C-3) and 33 mg (0.18 mmol) of 2-(chloromethyl)-1-methyl-1H-benzimidazole (31-1) was obtained the desired product 31-2 (TFA salt) as an amorphous fluffy white powder. MS M+=424. 1H NMR (CDCl3): 4.03 (s, 3H), 5.66 (s, 2H), 6.88 (d, 1H), 6.99 (m, 1H), 7.03 (dd, 1H), 7.14 (m, 1H), 7.35 (m, 1H), 7.45 (d, 1H), 7.49 (m, 3H), 7.93 (d, 1H).
Reaction SMILES: Br[CH:2](Br)[C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.Cl.CC[OH:23]>[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:23]
Reactant: CCOC(=O)c1nc(C(Br)Br)sc1-c1ccccc1
Reactant: CCO
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)c1nc(C=O)sc1-c1ccccc1

Procedure:
To a solution of an aqueous solution of the dibromo product (21b) obtained in Production Example 21 in EtOH was added an aqueous silver nitrate solution, followed by heating under reflux for 15 minutes. To the reaction liquid was added 1 M hydrochloric acid, the solid precipitated was removed by filtration, and the filtrate was then extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain ethyl 2-formyl-5-phenyl-1,3-thiazole-4-carboxylate as a pale yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH2:22][C:23]([N:25]1[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][O:27][C:26]1=[O:36])=[O:24])=[CH:15]2.[CH2:37](I)[CH:38]=[CH2:39]>C1COCC1>[CH3:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][C@H:22]([CH2:39][CH:38]=[CH2:37])[C:23]([N:25]1[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][O:27][C:26]1=[O:36])=[O:24])=[CH:15]2
Reactant: Cc1ccc2[nH]c(CCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)cc2c1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](Cc1cc2cc(C)ccc2[nH]1)C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a stirred solution of NaHMDS 1 M in THF (36.40 mL, 36.40 mmol) was added dropwise a solution of 8 (11.51 g, 33.04 mmol) in THF (180 mL) at −78° C. under argon. The solution was stirred at −78° C. (2 h), then allyl iodide (6.66 g, 39.65 mmol) in THF (70 mL) was added and the mixture was stirred for an additional 2 h at −78° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold saturated NH4Cl solution (200 mL), extracted with EtOAc, washed with brine and dried (Na2SO4). Evaporation provided a residue, which was purified by silica gel flash chromatography to provide 9 as colorless oil. (7.82 g, 61% yield). H NMR (d6-DMSO) δ 7.37-7.21 (m, 8H), 6.97 (dd, 1H, J=1.5 Hz & 8.5 Hz), 6.31 (dd, 1H, J=0.8 Hz & 3.1 Hz), 5.56 (m, 1H), 5.34 (dd, 1H, J=3.8 Hz & 8.5 Hz), 4.94-4.90 (m, 2H), 4.50 (t, 1H, J=8.7), 4.46-4.38 (m, 2H), 4.17 (m, 1H), 4.11 (dd, 1H, J=3.5 Hz & 8.8 Hz), 2.37 (s, 3H), 2.32 (m, 1H), 2.17 (m, 1H). FABMS (+Ve) m/z 388 [M+], 389 [MH+]. Anal. Calcd for C24H24N2O3 C, 74.21; H, 6.23; N, 7.21. Found C, 74.29; H, 6.22; N, 7.20.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].I[CH2:14][CH3:15]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH3:15])[N:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ncc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1ncc2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 5-bromo-1H-indazole (1 g, 5.10 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (330 mg, 8.25 mmol) at 0° C. with stirring for 30 min, iodoethane (1.72 g, 11.04 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford 5-bromo-1-ethyl-1H-indazole as yellow oil (598 mg, 52%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[Cl:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl.N>C(OCC)(=O)C>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=1[Cl:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A mixture of N-benzoyl 2-chloro-4-nitroaniline (5.77 g, 20.8 mmol) and tin (II) chloride (23.5 g, 104 .mmol) were heated in ethyl acetate (250 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature and concentrated aqueous ammonia (40 ml) was added. The reaction was filtered, the solid material was washed with ethyl acetate (3×30 ml) and the combined organic layers were evaporated in vacuo. Drying of the resultant solid in vacuo, yielded N-benzoyl 2-chloro-4-aminoaniline (4.63 g, 90% yield) as a cream-coloured crystalline solid:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[C:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:21][CH:20]=[C:19]([F:28])[N:18]=1.[Si:29]([O:36][C:37]1([CH2:41]/[CH:42]=[N:43]/[S@@:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[CH2:40][CH2:39][CH2:38]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N#N>C1COCC1>[Si:29]([O:36][C:37]1([CH2:41][C@H:42]([NH:43][S:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[C:20]2[C:19]([F:28])=[N:18][C:17]([F:16])=[C:22]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH:21]=2)[CH2:40][CH2:39][CH2:38]1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[S@@](=O)/N=C/CC1(O[Si](C)(C)C(C)(C)C)CCC1
Reactant: CC(C)(C)Cc1ccc(F)nc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc([C@H](CC2(O[Si](C)(C)C(C)(C)C)CCC2)NS(=O)C(C)(C)C)c(F)nc1F
Temperature: -78 °C
Yield: 13.5 %

Procedure:
To a three-necked RBF was added 2,2,6,6-tetramethylpiperidine (0.34 ml, 2 mmol), THF (10 mL), and an ethanol/N2 bath. After cooling to −78° C., butyllithium (0.70 ml, 2 mmol) was added dropwise. After stirring for several minutes, the solution was cooled to −100° C. of 2,6-difluoro-3-neopentylpyridine (0.230 g, 1 mmol) in THF (2 mL) was added dropwise. The solution was then treated with (R,E)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (0.71 g, 2 mmol) in THF (3 mL). After the addition was complete the reaction was allowed to warm to 0° C. as the liquid N2 boiled off. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 1% to 20% EtOAc in hexane, to provide N-((S)-2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.07 g, 11% yield). This material was used without further purification in the next step. MS m/z: 517 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>N1C=CC=CC=1.CO.O1CCCC1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:31]([CH:28]4[CH2:30][CH2:29]4)=[O:32])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([Cl:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(Cl)cc1F
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}carbamate (1.30 g, 3.16 mmol) in pyridine (20 mL) was added cyclopropanecarbonyl chloride (345 μL, 3.80 mmol), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed successively with water (50 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (10 mL)/tetrahydrofuran (10 mL), sodium carbonate (335 mg, 3.16 mmol) was added, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added aqueous ammonium chloride solution (30 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→50/50) to give the title compound (1.22 g, 81%) as a white powder.