Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][OH:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:21]=1.Br[CH2:26][C:27]#[C:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][O:24][CH2:26][C:27]#[C:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[N:21]=1
Reactant: BrCC#Cc1ccccc1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCC#Cc3ccccc3)c2c1C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
Sodium hydride (0.82 g, 20.48 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (20 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (5.8 g, 19.50 mmol) from Part G in N,N-dimethylformamide (30 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of 3-bromo-1-phenylpropyne (4.18 g, 21.45 mmol) from Part A in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60% in mineral oil) and then 3-bromo-1-phenylpropyne (1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 7% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a brown solid, which was triturated with diethyl ether. The resulting solid was filtered off, and a second crop was collected from the mother liquor. The combined solids were passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. A white solid (5.4 g) was isolated and carried on to the next step. HPLC analysis indicated the presence of about 9% starting material in the white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11].[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(F)cccc1F)[C@@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 3-(2,6-difluorophenylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (90 mg, 232 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol, Eq: 112) and the resulting solution stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and the residue azeotroped with n-heptanes to give (S)—N-(2,6-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide trifluoroacetate which was used without purification (93 mg), m/z=289 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.[C:28]1([CH3:36])[C:29]([CH:34]=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH3:36])[OH:35])=[N:11][N:10]=[N:9]2)=[CH:13][CH:14]=1
Reactant: Cc1ccccc1C=O
Reactant: COc1ccc(Cn2cnnn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2C(O)c2ccccc2C)cc1
Temperature: -85 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A stirred solution of 1-(4-methoxybenzyl)tetrazole (7.04 g, Tetrahedron Letters, 1995, p1759-1762) in a mixture of dry tetrahydrofuran (120 ml) and N,N,N',N',-tetramethylethylenediamine (12 ml) under a nitrogen atmosphere at -85° C. was treated dropwise with n-butyl lithium (18 ml, 2.5M solution in hexanes) over 10 minutes. After stirring at -85° C. for an additional 5 minutes a solution of o-tolualdehyde (4.45 g) in dry tetrahydrofuran (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at -85° C. for 30 minutes, allowed to warm to room temperature, then quenched with saturated ammonium chloride solution (50 ml). The organic phase was separated and the aqueous phase extracted three times with ethyl acetate (100 ml). The combined organic phases were dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:1, v/v) then with a mixture of ethyl acetate and pentane (66:34, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (9.8 g) as a white solid, m.p. 90-92° C. [Elemental analysis:- C,65.91, H,5.9, N,18.1%. Calculated:- C,65.79, H,5.85, N,18.05%].
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[N:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of methyl 3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 0.18 mmol) in methanol (0.9 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to pH=6. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/−)-3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoic acid (52 mg, 59%). 1HNMR (400 MHz, CD3OD, δ): 8.47 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 6.92 (d, 2H), 5.34 (m, 1H), 3.53 (m, 2H), 2.48 (m, 2H), 1.98-1.94 (m, 1H), 1.60-1.58 (m, 1H), 0.75-0.77 (m, 1H), 0.42-0.33 (m, 2H), 0.08-0.01 (m, 2H). MS (M+Na): 510.3.
Reaction SMILES: C1COCC1.Br.[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[S:23][CH:24]=3)[CH:11]=[CH:10][C:9]1=2.O=[CH:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([C:20]3[N:21]=[C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:33][CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:27][CH2:26]4)[S:23][CH:24]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 ml of THF and 200 μl of glacial acetic acid are added to 200 mg (0.46 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrobromide, and 154 mg (0.92 mmol) of tert-butyl (2-oxoethyl)carbamate are added. 195 mg (0.92 mmol) of sodium trisacetoxyborohydride are subsequently added, and the reaction mixture is stirred at room temperature for 24 h. The reaction mixture is filtered, the mother liquor is evaporated, and the residue is purified by preparative HPLC, giving “A37”;
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[CH2:4][C:3](=[O:8])[CH2:2]2.[NH2:9]OS(O)(=O)=O.[OH-].[Na+]>C(O)=O>[O:8]=[C:3]1[CH2:4][CH:5]2[CH:1]([CH2:7][CH2:6]2)[CH2:2][NH:9]1
Reactant: O=C1CC2CCC2C1
Reactant: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1CC2CCC2CN1
Temperature: 0 °C
Yield: 8.8 %

Procedure:
To a solution of 0.48 g of bicyclo[3.2.0]heptan-3-one in 8 ml of formic acid was added 725 mg of hydroxylamine-O-sulfonic acid, followed by heat-refluxing for 3 hours. The reaction mixture was allowed to cool, poured into ice water, neutralized with a 5N sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 48 mg of the title compound as a brown solid, which had the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33](C(OC(C)(C)C)=O)[CH:32]=[CH:31]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([N:24]5[CH2:25][CH2:26][CH2:27][C:23]5=[O:22])=[CH:36][CH:35]=4)[CH:31]=[CH:32]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(N3CCCC3=O)ccc21
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(N5CCCC5=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and tert-butyl 5-(2-oxopyrrolidin-1-yl)-1H-indole-1-carboxylate (intermediate-27) (0.011 g, 6%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21](C)(C)[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[K+].[Br-]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=Cc2cnc(N)c(C#N)c2)cc1
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1ccc(C=Cc2cnc(N)c(C#N)c2)cc1

Procedure:
By substituting an equivalent amount of 3-cyano-2-(4-nitrophenylthio)-5-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyridine in the foregoing procedure there is obtained 2-amino-3-cyano-5-[2-(4-tert-butoxycarbonylphenyl)ethenyl]pyridine, which can be alternatively named as 2-amino-3-cyano-5-(4-t-butoxycarbonylstyryl)pyridine; yield 1.14 g (84%) of light yellow crystals, mp 190°-195° C.; NMR (Me2SO-d6) delta 1.57 (s, 9H), 6.57-6.60 (m, 2H), 7.00 (br, 2H), 7.35 (d, 2H, J=8.1 Hz), 7.65 (d, 1H, J=2.7 Hz), 7.84 (d, 2H, J=8.1 Hz), 8.00 (d, 1H, J=2.7 Hz); IR (KBr) 3460, 3360, 2215, 1707, 1623, 1480, 1300, 1287, 1158 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH2:36][CH2:37][O:38][CH2:39][CH:40]=1)CCC>>[O:38]1[CH2:37][CH:36]=[C:35]([C:2]2[N:7]=[C:6]3[CH2:8][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:12])[CH2:10][C:5]3=[CH:4][CH:3]=2)[CH2:40][CH2:39]1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(Cl)nc2C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccc(C3=CCOCC3)nc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example A54(a) from (2-chloro-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (Example C4) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. White solid. MS (m/e): 497.4 [M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:13].[Br:15]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][Br:15]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
Into a stirring solution of methyl-2-methyl-6-nitrobenzoate (3.9 g, 20 mmols) in 50 mL CCl4 anhydrous, N-bromosuccinamide (3.56 g, 20 mmols), and benzoylperoxide (25 mg, 0.10 mmols), was added. The reaction mixture was heated under reflux for about 24 hours. TLC developed in EtOAc/Hex 1:9 mixture showed formation of new product. The CCl4 was evaporated and on leaving a viscous product at RT, light yellow crystals of product were separated. The product was purified by flash silica gel column eluted with Hex/EtOAc. 9:1 mixture to give 3.0 g light yellow crystals (70%). A small portion of dibrominated product was also separated. 1H NMR in CDCl3 confirmed the product as methyl-2-bromomethyl-6-nitrobenzoate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:21][OH:22])[N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]2.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH:21]=[O:22])[N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:7]2
Reactant: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H](CO)C2
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Br)c2c1CN(C(=O)OC(C)(C)C)[C@@H](C=O)C2
Temperature: 0 °C
Yield: 97.7 %

Procedure:
Dissolve the tert-butyl 5-bromo-3(R)-(hydroxymethyl)-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (710 mg, 0.0019 mol) in dimethylsulfoxide (2.00 mL) and cool to 0° C. Add triethylamine (1.06 mL, 0.00763 mol) and sulfur trioxide-pyridine complex (0.607 g, 0.00381 mol). Warm to room temperature over one hour. Dilute diethyl ether (100 mL) and extract (3×25 mL) with 5% aqueous citric acid, (1×25 mL) saturated aqueous sodium chloride, and dry over magnesium sulfate. Concentrate the filtrate to give the desired product (687 mg, 94%) as an off-white semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([NH:12][NH:13][C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22][CH2:23]3)=[O:28])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NNc1cnc2ccc(Br)cc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNc2cnc3ccc(Br)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
A mixture of 7-bromo-2-hydrazinylquinoxaline (3 g, 12.55 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.16 g, 13.81 mmol), EDCI (2.89 g, 15.06 mmol), HOBt (2.03 g, 15.06 mmol), and TEA (1.9 g, 18.83 mmol) in DMF (100 mL) was stirred at r.t. overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (3×100 mL). The combined layers were dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-(2-(7-bromoquinoxalin-2-yl)hydrazinecarbonyl)piperidine-1-carboxylate as pale yellow solid (3.5 g, yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.C1(C)C=CC=CC=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 490.9 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-phenylamine (0.07 g, 0.29 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (0.22 g, 1.3 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was precipitated from methanol to give N-({[3-fluoro-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)-2-phenylacetamide as a white solid (0.6 g, 50% yield). 1H NMR (400 MHz, DMSO): 12.49 (s, 1H), 12.35 (s, 1H), 12.82 (s, 1H), 8.32 (s, 1H), 7.89 (dd, 1H), 7.53 (t, 1H), 7.42 (d, 2H), 7.34 (d, 4H), 7.29 (m, 1H), 7.19 (d, 1H), 6.64 (d, 1H), 3.82 (s, 2H); MS (ESI) for C21H16FN5O2S: 422 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:9]=1[OH:10])[CH:2]=[CH2:3].[I:28]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:7]2[N:8]([C:9]3[O:10][CH:2]([CH2:3][I:28])[CH2:1][C:4]=3[CH:5]=[N:6]2)[N:11]=1
Reactant: C=CCc1cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn2c1O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c4c(cnc23)CC(CI)O4)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-allyl-3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-15A-1a; 25 mg, 0.063 mmol) in 9:1 methylene chloride/chloroform (0.63 ml) at 0° C. was added N-iodosuccinimide (15 mg, 0.066 mmol), portionwise. The reaction was stirred overnight at room temperature and then extracted from water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo. Purification on a Biotage™ Flash 12S column using 20% ethyl acetate in hexanes as eluant afforded compound 15A-1 (15 mg, 46%) as a solid: +ESI MS (M+1) 522.3; 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.53–7.40 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 5.45–5.41 (m, 1H), 3.81–3.64 (m, 2H), 3.33 (d, J=6.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.[CH2:31]([O:35][C:36](Cl)=[O:37])[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:31]([O:35][C:36](=[O:37])[NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccc(NC(=O)OCC(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in CH2Cl2 (0.5 mL) is added 4-dimethylaminopyridine (17 mg, 0.136 mmole). The reaction mixture is cooled to 0° C. and isobutylchloroformate (18 μL, 0.136 mmole) is added dropwise. The reaction mixture is stirred at room temperature 2 h, diluted with water and made alkaline with 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC over silica gel eluting with (acetone:NEt3) to afford {4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-carbamic acid isobutyl ester melting at 196° C.
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][CH:8]=1)#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:2])=[O:12])=[CH:9][CH:8]=1)#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1ccc(C(=O)O)cc1
Yield: 94.2 %

Procedure:
Sodium nitrite (2.07 g) was dissolved in a 70 wt. % aqueous sulfuric acid solution (100 ml), and p-cyanobenzamide (2.92 g) was added to the resultant solution. The mixture was allowed to react at room temperature for one hour with stirring. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.77 g of p-cyanobenzoic acid (yield 95%). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:9]=2)[C:5]([CH3:15])([CH3:14])[CH2:6]1)(=[O:13])[CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CC(C)(C)c2cc(F)ccc21
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21

Procedure:
1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (1.1 g, 6.0 mmol) was treated with chlorosulfonic acid (10 mL) following similar methods to those described in Preparation 63) to give the desired compound (900 mg) as a grey solid. 1H NMR (Acetone-d6): 8.76 (1H, d), 7.54 (1H, d), 4.10 (2H, s), 2.32-2.23 (3H, m), 1.48 (6H, s).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2I.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 5-difluoromethoxy-3-iodo-1H-indazole (200 mg, 0.6 mmol) was dissolved in THF (3.6 ml) and sodium hydride (60% in mineral oil, 64 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.46 ml, 0.920 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.22 ml, 0.81 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h then quenched with saturated NH4Cl— solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 5-difluoromethoxy-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.