Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.Cl.[NH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:31]=[C:28]1[CH2:29][CH2:30][N:25]([CH2:12][CH2:13][CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)[CH2:26][CH2:27]1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCN(CCC2COc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 10 g of 4-piperidone hydrochloride, 20 g of anhydrous sodium carbonate and 160 ml of dimethylformamide is stirred vigorously at room temperature for 48 hours. It is filtered, the residue washed with a small amount of dimethylformamide and the filtrate evaporated. The residue is dissolved in ethyl acetate, the solution extracted with hydrochloric acid, the extract made alkaline with 50% aqueous sodium hydroxide while cooling and re-extracted with methylene chloride. The latter extract is dried and evaporated, to yield the 2-[2-(4-oxopiperidino)-ethyl]-1,4-benzodioxan, which solidifies on standing.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.O[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:17]([O:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]3[CH2:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=3[CH:10]=2)=[O:14])=[CH:18][CH:19]=1)[CH3:25]
Reactant: CC1(C)CCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCC3)cc1

Procedure:
A solution of 220.7 mg (1.0804 mmol) of 8,8-dimethyl-5,6,7,8-tetrahydro-2-naphthoic acid, 180.6 mg (1.0868 mmol) of ethyl 4-hydroxybenzoate, 227.3 mg (1.1034 mmol) of 1,3-dicyclohexylcarbodiimide and 22.9 mg (0.1874 mmol) of 4-dimethylaminopyridine in 15 ml of methylene chloride was stirred at room temperature for 18 h. The reaction mixture was then filtered and the residue washed with 10 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a colorless oil. PMR (CDCl3): δ 1.35 (6H, s), 1.42 (3H, t, J~7.2 Hz), 1.68-1.76 (2H, m), 1.80-1.92 (2H, m), 2.85 (2H, t, J~6.1 Hz), 4.40 (2H, q, J~7.2 Hz), 7.18 (1H, d, J~ 8.0 Hz), 7.31 (2H, d, J~8.7 Hz), 7.89 (1H, dd, J~8.0 Hz, 1.6 Hz), 8.11-8.22 (3H, m).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[NH:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23]Cl)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][N:3]3[C:4](=[O:7])[CH2:5][CH2:6][C:2]3=[O:1])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: O=C1CCC(=O)N1CCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
Scheme-I: A mixture of 2,5-dioxopyrrolidine (0.500 g, 5 mmol), 1-[4-(4-fluorophenyl)-piperazin-1-yl]-3-chloropropane (1.28 g, 5 mmol), potassium carbonate (0.502 g, 3.75 mmol) and tetrabutylammonium bromide (0.322 g, 1 mmol) in acetone (25 ml) was refluxed for 16 hours at 80° C. with stirring. The solvent was evaporated off in vacuo and the residue was suspended in water (80 ml). The aqueous solution was extracted with chloroform (3×50 ml), and the organic layers combined, washed with water (2×50 ml), dried over Na2SO4 and evaporated in vacuo to give the title compound. The product was purified by column chromatography over flash silica gel using chloroform-methanol (98:2) as eluent; yield 1.00 g (65%), oil.
Reaction SMILES: C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1(O)C=CC=CC=1.C1(O)C=CC=CC=1.C(OC1C=CC=CC=1)=O.C(OC1C=CC=CC=1)=O.[CH:49]1[C:54]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N:62]=C=O)=[CH:58][CH:57]=2)=[CH:53][CH:52]=[C:51]([N:65]=C=O)[CH:50]=1.C(OC1C=CC=CC=1)(=O)N>C(O)=O>[CH2:55]([C:56]1[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=1)[C:54]1[CH:53]=[CH:52][C:51]([NH2:65])=[CH:50][CH:49]=1
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Agent: NC(=O)Oc1ccccc1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=COc1ccccc1
Solvent: O=CO
Solvent: Oc1ccccc1
Product: Nc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
The di-formamide of 4,4′-methylene-dianiline is prepared by the reaction of the diamine with 2.1 molar equivalents of formic acid, and removing the water byproduct by azeotropic distillation with toluene. Using the same apparatus as Example 1, but without the addition funnel, diphenyl carbonate (48.45 grams, 0.226 mole) and 4,4′-MDA-di-formamide (6.92 grams, 0.0272 mole), containing 0.21 grams of phenol, is heated to reflux at 38 mmHg. Reaction and phenol/phenyl formate distillation commences at a pot temperature of 155° C., and ceases 30 minutes later at a pot temperature of 195° C., 17 mmHg. IS/GC analysis of the condensate (10.55 grams) shows only phenyl formate, phenol and a trace of DPC. The pot material (43.97 grams) contains 3.02 grams of 4,4′-diphenylmethane diisocyanate (MDI) and 3.21 grams of MDI as the mono-phenol carbamate, a recovery of 0.0249 mole equivalents of MDI, equal to a 91.6% yield, based on di-formamide charged.
Reaction SMILES: [CH2:1]1[O:23][C:4]2[CH:5]=[C:6]([O:9][CH2:10][CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[CH:8][C:3]=2[O:2]1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[O:32]1[C:16]([CH3:21])([CH2:17][CH:18]([CH3:19])[CH3:20])[CH:15]1[CH2:14][CH2:13][C:12]([CH3:22])=[CH:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:23][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=CCOc1ccc2c(c1)OCO2)CCC=C(C)CC(C)C
Solvent: ClCCl
Product: CC(=CCOc1ccc2c(c1)OCO2)CCC1OC1(C)CC(C)C

Procedure:
To 10 g. of 1,2-(methylenedioxy)-4-[(3,7,9-trimethyl-2,6-decadienyl)oxy]-benzene dissolved in 100 ml. of methylene chloride are added portionwise, while stirring and cooling with ice at 1°-5° C., 6.85 g. of 80% m-chloroperbenzoic acid and the mixture is stirred for a further 2 hours while cooling with ice. The mixture is subsequently diluted with 200 ml. of ether and washed successively with ice-cold 1-N aqueous sodium hydroxide, water and saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated. By chromatography on silica gel with hexane/ether (4:1 parts by volume), there is obtained pure 4-[(6,7-epoxy-3,7,9-trimethyl-2-decenyl)-oxy]-1,2-(methylenedioxy)-benzene of boiling point (bulb tube) 135°-140° C./0.02 mm Hg.; nD22 = 1.5168.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[N:8][NH:9][C:10](=O)[C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:10]1[N:9]=[N:8][CH:7]=[C:6]2[O:1][CH2:2][CH2:3][CH2:4][C:5]=12
Reactant: O=c1[nH]ncc2c1CCCO2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nncc2c1CCCO2
Temperature: 25 °C
Yield: 59.5 %

Procedure:
3,4-Dihydro-2H-pyrano[2,3-d]pyridazin-5(6H)-one (400 mg, 2.63 mmol) was stirred in phosphorus oxychloride (4 mL, 6.58 g, 42.9 mmol) at 95° C. for nearly 2 hours. The reaction was then cooled to room temperature and excess phosphorus oxychloride was removed in vacuo. The residue was treated with ice (˜15 g) and very slowly with solid potassium carbonate until pH >7. A tan solid was isolated by filtration and dried under vacuum to afford the title compound (267 mg, 57% yield). MS (ESI) [m/e, (M)+]=170.6. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68 (s, 1H), 4.28-4.42 (m, 2H), 2.78 (t, J=6.32 Hz, 2H), 2.05-2.20 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH2:5][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC2CCCCO2)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a pre-stirred solution of 2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzaldehyde (2.14 g, 8.6 mmol) and piperidine (0.93 mL, 9.4 mmol) in DCM (35 mL) at 0° C. was added sodium triacetoxyborohydride (2.72 g, 12.8 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (30 mL) and ethyl acetate (75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (2.78 g, quantitiative yield) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 6.51 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 5.40 (t, J=3.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s, 3H), 3.64-3.55 (m, 1H), 3.39 (s, 2H), 2.42-2.27 (m, 7H), 2.07-1.93 (m, 1H), 1.90-1.77 (m, 2H), 1.75-1.52 (m, 3H), 1.54-1.44 (m, 4H), 1.43-1.34 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]3[C:14]4=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]4[CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
A mixture of 4-chlorophenylboronic acid (407 mg), 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (240 mg), diacetoxycopper (316 mg), triethylamine (0.604 mL), and powdered 4A MS (1.5 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (132 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:22][O+](C)C>>[CH3:22][O:16][C:14]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:15]=1
Reactant: O=C1CCCC(CCCc2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(CCCc2ccccc2)CCC1

Procedure:
The product of Example 99 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](OC)(=[O:11])[CH3:10].[Na].CC1C=C(C)N=C(O)C=1>CC(N(C)C)=O>[CH2:1]([NH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)=O
Reactant: NCc1ccccc1
Agent: Cc1cc(C)nc(O)c1
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CC(=O)NCc1ccccc1
Yield: 84 %

Procedure:
2.1 g. of benzylamine, 7.4 g. of methyl acetate and 1.5 g. of the sodium salt of 4,6-dimethyl-2-hydroxypyridine are dissolved in 30 ml. of dimethyl acetamide and heated at about 78° C. for 4.5 hours. As determined by thin layer chromatography, all but a trace of the benzylamine is consumed. 200 ml. of water and 0.9 ml. of concentrated hydrochloric acid are added to the reaction solution, and the solution is extracted three times with 100 ml. of ethyl acetate. The organic layer is washed with 100 ml. of water, and, after drying with sodium sulfate, concentrated and crystallized. After recrystallization from 300 ml. of ether-petroleum benzin (1:1), 2.5 of needle-like crystals of N-benzyl acetamide are obtained (yield: 84%).m.p. 60.5° - 62° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(OCC)C>[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:12]2[C:13]([NH:15][C:16](=[O:17])[C:11]=12)=[O:14]
Reactant: O=C1NC(=O)c2c(CCCCCCCCBr)cccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCNCC1CCCCCCCCc1cccc2c1C(=O)NC2=O

Procedure:
8-Bromooctylphthalimide (516 mg; 2.0 mmoles) and N-methylpiperazine (0.44 ml; 4.0 mmoles) were dissolved to anhydroius ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].[CH2:25]([C:28]1[CH:37]=[C:36]2[C:31](CCC(=O)N2CC=CC2C=CC=CC=2)=[CH:30][C:29]=1O)[CH:26]=[CH2:27].[Br-]>CO.[OH-].[K+]>[CH2:1]([C:4]1[C:13]([O:14][CH2:27][CH:26]=[CH:25][C:28]2[CH:37]=[CH:36][CH:31]=[CH:30][CH:29]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2c1CCC(=O)N2CC=Cc1ccccc1
Reactant: C=CCc1cc2c(cc1O)CCC(=O)N2CC=Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCC=Cc2ccccc2)ccc2c1CCC(=O)N2CC=Cc1ccccc1
Yield: 41.4 %

Procedure:
3.19 Grams of the mixture of 5-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and 7-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained in Example 13 was dissolved in 100 ml of methanol containing 1 g of potassium hydroxide. Under stirring, 2 g of cinnamy bromide was added thereto at room temperature, then stirred at room temperature for 1 hour, further stirred at 60° C. for 4 hours. After the reaction was finished, the reaction mixture was concentrated to a half volume under reduced pressure, 100 ml of water was added and stirred vigorously, then extracted with 200 ml of ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness. The residue was subjected to treatment by means of a silica gel flush column chromatography by using a mixed solvent of ethyl acetate: n-hexane as the eluent. The second eluted portion was collected and concentrated and crystallized from diethyl ether-n-hexane, there was obtained 1.8 g (41.4%) of 5-allyl-1-cinnamyl-6-cinnamyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless granular crystals (recrystallized from diethyl ether-n-hexane). Melting point: 66°-68° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 69.2 %

Procedure:
5-Bromo-2-hydroxy-benzoic acid (5 g, 23.04 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (6.56 g, 34.5 mmol) as desribed in general procedure D. The crude product was then was then purified by silica gel column chromatography (ethyl acetate:hexanes from 20:80 to 60:40) to afford 4.5 g of the 4-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.CC([NH:16][C:17]1[C:22]2[CH:23]=[CH:24][N:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:21]=2[CH:20]=[CH:19][N:18]=1)(CC(C)(C)C)C>ClCCl>[NH2:16][C:17]1[C:22]2[CH:23]=[CH:24][N:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:21]=2[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)CC(C)(C)Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added drop wise to an ice-cooled suspension of benzyl 4-[(2,4,4-trimethylpentan-2-yl)amino]-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5 g, 9.7 mmol, Step c) in dichloromethane (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue was stirred in excess aqueous ammonia solution. The precipitated solid was filtered under suction, washed with water and dried to yield benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.5 g, 95%) as off-white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]#[N:35])=[CH:24]1)[CH3:22].[CH2:36]([Sn:40](I)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[CH2:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]#[N:35])=[C:24]1[Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])[CH3:22]
Reactant: CCn1cc(C#N)c2ccc(OC)cc21
Reactant: CCCC[Sn](I)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1c(C#N)c2ccc(OC)cc2n1CC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) was cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) was added dropwise over 5 minutes. The LDA mixture was stirred at −78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solution was re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example 1A, was taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction was stirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Once again, the reaction mixture was cooled to −78° C. Tributyltin iodide (10 mL, 35 mmol) was added dropwise. This was stirred at −78° C. for 15 minutes, and then at 0° C. for 30 minutes. The reaction mixture was absorbed onto silica gel and concentrated. Purification by chromatography (CH2Cl2) yielded 1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g, 98%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH2:6][C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=2)[CH2:3]1.Br[CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>C1COCC1>[NH2:16][C:11]1[C:10]2=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:21]=4)[CH:8]=[C:7]([CH2:6][CH:4]3[CH2:5][N:2]([CH2:34][CH2:35][OH:36])[CH2:3]3)[N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnn2c(CC3CN(CCO)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 60 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in THF (1.5 mL) was added (2-bromoethoxy)-tert-butyldimethylsilane (53 μL, 0.25 mmol) and N,N-diisopropylethylamine (117 μl, 0.67 mmol). The reaction was heated (60° C.) for 17 h and then cooled to rt. The crude mixture was purified by preparative HPLC using a gradient elution from 20% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated. A solution of the residue in 1% HCl in 95:5 EtOH/H2O (4 mL) was stirred at rt for 16 h. The mixture was basified (pH 9) with the addition of saturated, aqueous NaHCO3 solution and was evaporated to remove volatiles. The remaining aqueous mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to afford 6 mg (6%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1 H), 8.17 (s, 1 H), 7.83 (d, 1 H), 7.67 (s, 1 H), 7.26-7.39 (m, 5 H), 7.14 (d, 1 H), 6.77 (d, 1 H), 5.66 (s, 2 H), 4.11-4.27 (m, 2 H), 3.89-4.02 (m, 3 H), 3.53-3.63 (m, 2 H), 3.33-3.42 (m, 1 H), 3.10-3.30 (m, 4 H); ES-MS m/z 454.46 [M+H]+, HPLC RT (min) 1.96.
Reaction SMILES: O[N:2]=[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])[CH3:4].[ClH:17]>CO.[Pd]>[ClH:17].[NH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:16])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)=NO)c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C(C)N)c(OC)c1
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a degassed solution of methyl 4-(1-(hydroxyimino)ethyl)-3-methoxybenzoate (0.417 g, 1.87 mmol) in methanol (17 mL) was added 12.0 M aqueous hydrochloric acid (0.389 mL, 4.67 mmol) and 10% palladium on carbon (0.120 g, 0.113 mmol). The reaction mixture was stirred under a balloon atmosphere of H2 overnight. The catalyst was removed via filtration through celite and evaporation of the filtrate to dryness afforded the title compound (0.471 g, 100%). LC-MS: (FA) ES+ 209; 1H NMR (300 MHz, DMSO) δ 8.20 (s, 3H), 7.64 (m, 1H), 7.55 (s, 2H), 4.60 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 1.46 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>>[F:1][C:2]1([F:21])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:31])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH3:12]
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(I)ccc2F)C1(F)F
Yield: 95.3 %

Procedure:
In a manner analogous to that described for the preparation of intermediate B7, the reaction of (R)-6,6-difluoro-5-(2-fluoro-5-iodo-phenyl)-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate B6″.1) (1.455 g, 3.52 mmol) with Lawesson's reagent (1.42 g, 3.52 mmol), yielded the title compound (1.44 g, 95% yield) as a colorless oil. MS (ISP): m/z=430.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:4]([NH2:17])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:8]=1.C1C(=O)N([I:27])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[C:4]([NH2:17])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16]([I:27])[N:11]3[N:10]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncc(-c2nn3ccnc3s2)cc1C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
3-(trifluoromethyl)-5-(imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.244 g, 0.855 mmol, 1 eq) was dissolved in DMF (5 mL), and NIS (0.212 g, 0.941 mmol, 1.1 eq) was added. The reaction mixture was stirred at RT under N2 for 18 h and then poured into an aqueous solution of sodium thiosulfate (10%) and extracted with AcOEt. The organic phase was separated, washed with ice-water and ammonium chloride, dried (Na2SO4), filtered and evaporated to dryness. The residue was treated with Et2O, filtered off and dried affording the desired product (0.240 g, 68%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.27 min, [M+H]+ m/z 411.9.