Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:41])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].[N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=[C:44]([CH:52]=O)[CH:43]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:41])/[C:12](/[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33])=[CH:52]/[C:44]1[CH:43]=[N:42][C:51]2[C:46]([CH:45]=1)=[CH:47][CH:48]=[CH:49][CH:50]=2
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (30 μL, 0.24 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 132; 55 mg, 0.11 mmol) in tetrahydrofuran (2 mL) at room temperature. After 5 min, quinoline-3-carboxaldehyde (18 mg, 0.114 mmol) was added and the solution was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and the residue was dissolved in a solvent mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and evaporated to dryness. A solution of the residue in a minimum amount of chloroform/methanol/water/acetic acid (150:30:10:6) was applied to a column of three piggy-backed SepPak Plus® silica gel cartridges that had been pre-washed with chloroform. The column was eluted with chloroform, then with a mixture of chloroform/methanol/water/acetic acid (300:30:10:6). Evaporation of the appropriate fractions gave (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (32.7 mg, 55% yield) as a colorless powder.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:28]=[C:27]([NH:29][CH2:30][C@@H:31]5[O:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]5)[C:26]5[C:21](=[N:22][CH:23]=[CH:24][N:25]=5)[CH:20]=4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.CC(=O)OCC>CC(=O)OCC>[CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[N:28]=[C:27]([NH:29][CH2:30][C@H:31]5[O:36][CH2:35][CH2:34][NH:33][CH2:32]5)[C:26]5[C:21](=[N:22][CH:23]=[CH:24][N:25]=5)[CH:20]=4)=[CH:17][CH:18]=3)[CH2:9][CH2:8]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CNc2nc(-c3ccc(N4CCN(S(=O)(=O)C5CC5)CC4)cc3)cc3nccnc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CNCCO4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.2 %

Procedure:
A solution of (S)-tert-butyl 2-((7-(4-(4-(cyclopropylsulfonyl)piperazin-1-yl)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (52 mg, 0.09 mmol) and 2 mL of HCl-EA (5.0 N) in 5 mL of EA, was stirred at room temperature for 1 hour. The volatiles were removed in vacuo, and the residue was added to 5 mL of MeOH and 0.5 mL of NH3.H2O, was stirred at room temperature for 10 minutes. The volatiles were removed in vacuo, and the residue was purified by chromatography with MeOH/H2O (1:6˜5:1) to give 18 mg title compound. MS (m/z)=510 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:6][CH3:7].C[O-].[Na+]>CO>[CH2:5]([CH:4]1[NH:8][S:9](=[O:11])(=[O:10])[NH:12][C:3]1=[O:2])[CH2:6][CH3:7]
Reactant: CCCC(NS(N)(=O)=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O

Procedure:
A solution of 2-(aminosulfonylamino)pentanoic acid methyl ester (24.6 g; 0.117 retool) in methanol (150 ml) was added to a solution of sodium methoxide (8.86 g, from 3.77 g of Na) in 150 ml of methanol and the resulting reaction mixture was refluxed for 18 hours. The mixture was cooled, neutralized with BIO-RAD® 50W-X8 H+ ion exchange resin, and filtered. The filtrate was concentrated in vacuo to yield an oil which was crystallized from methanol/hexane to afford 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H; R2 =propyl; R3 =H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15]C>N1CCCCC1.C(O)C>[CH2:12]([C:11]1[N:5]2[N:6]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:7]=[C:9]([CH3:8])[CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)CC(C)=O
Reactant: Cc1cc(N)[nH]n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCc1cc(C)nc2cc(C)nn12
Temperature: 80 °C

Procedure:
Add 5-methyl-2H-pyrazol-3-ylamine (217 mg, 2.17 mmol), nonane-2,4-dione (339 mg, 2.39 mmol) and piperidine (1 drop) to ethanol (10 mL) and heat at 80° C. overnight. Cool to room temperature and concentrate to dryness. Purify by silica gel column chromatography (0-20% ethyl acetate in hexane) to obtain a mixture of two isomers (2 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1.[OH-].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc(Nc2ccccc2F)[nH]c1=O
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic aicd, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (70 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.1 g). M.p. 300° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6](OS(C)(=O)=O)([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)[CH3:7].CN(C=O)C>C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[N:1]([C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:7])[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1cccc2c(C(C)(C)OS(C)(=O)=O)ncnc12
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2c(C(C)(C)N=[N+]=[N-])ncnc12
Reaction time: 96 h

Procedure:
Sodium azide (492 mg, 7.57 mmol) is added to methanesulfonic acid 1-methyl-1-(8-methyl-quinazolin-4-yl)-ethyl ester (680 mg, 78% content, 1.89 mmol) in DMF (1.5 mL, 19.56 mmol) and stirring is continued for 4 d. The reaction mixture is diluted with saturated Na2CO3 and EtOAc. The organic layer is washed with brine, dried and filtered to give 4-(1-azido-1-methyl-ethyl)-8-methyl-quinazoline (as a solution in EtOAc).
Reaction SMILES: C([NH:8][CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([O:28]CC2C=CC=CC=2)=[C:23]([NH:25][CH:26]=[O:27])[CH:24]=1)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])C1C=CC=CC=1.[C:36]([OH:39])(=[O:38])[CH3:37]>CO>[C:36]([OH:39])(=[O:38])[CH3:37].[NH2:8][CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([NH:25][CH:26]=[O:27])[CH:24]=1)[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCc1ccccc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NC=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.8 %

Procedure:
Crude N-{5-[(R)-2-benzylamino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-benzyloxyphenyl}formamide (100 g, 194 mmol) was dissolved in methanol (1 L) and acetic acid (25 mL, 291 mmol). The resulting mixture was purged with dry nitrogen and then palladium hydroxide on carbon (20 g, 20 wt. %, about 50% water) was added. Hydrogen was bubbled through the reaction mixture with stirring at room temperature for about 10 hours. The mixture was then purged with dry nitrogen and the mixture was filtered through Celite. The filtrate was concentrated on a rotary evaporator and ethyl acetate (600 mL) was added to the residue. This mixture was stirred for about 2 hours at which time a thick yellow slurry had developed. The slurry was filtered and the precipitate was air dried to provide N-{5-[(R)-2-amino-1-(tert-butyldimethylsilanyloxy)ethyl]-2-hydroxyphenyl}formamide acetic acid salt (48 g, 98% purity) as a yellow-white solid. LCMS (10-70) Rt=3.62; [M+H+] found 311.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][CH2:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]([C:17]([OH:19])=O)[C:7]=2[CH:20]=1.[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:25]=1[NH2:26])([CH3:23])[CH3:22]>>[CH:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:24]([CH:21]([CH3:23])[CH3:22])[C:25]=1[NH:26][C:17]([CH:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:15][O:16][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][C:7]1=2)=[O:19])([CH3:33])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: COc1ccc2c(c1)C(C(=O)O)c1cccnc1CO2
Product: COc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1cccnc1CO2
Yield: 73.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 0.74 g of 5,11-dihydro-7-methoxybenzoxepino[3,4-b]pyridin-5-carboxylic acid obtained in Example 58 (Compound W) in place of Compound A and 0.72 g of 2,6-diisopropylaniline in place of aniline to obtain 0.86 g of Compound 41.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([Cl:15])=[C:8]([C:11]([Cl:14])=[CH:12][N:13]=1)[C:9]#[N:10].[F:16][B-](F)(F)F.[H+]>>[Cl:15][C:7]1[C:6]([F:16])=[N:13][CH:12]=[C:11]([Cl:14])[C:8]=1[C:9]#[N:10]
Reactant: F[B-](F)(F)F
Reactant: N#Cc1c(Cl)cnc(N)c1Cl
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: N#Cc1c(Cl)cnc(F)c1Cl
Yield: 36.5 %

Procedure:
Sodium nitrite (3.17 g, 46.0 mmol) was added in small portions to a suspension of crude 2-amino-3,5-dichloroisonicotinonitrile (4.32 g) in tetrafluoroboric acid (60 mL, 806 mmol) at −10° C. over 1 h. The resultant mixture was stirred at −10° C. for 1 h, carefully quenched with ice and solid Na2CO3 and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), concentrated to ˜20 mL in volume, triturated with dichloromethane (30 mL) and filtered. The filtrate was concentrated and purified by silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5 to 30% ethyl acetate in hexanes, to give 3,5-dichloro-2-fluoroisonicotinonitrile (1.60 g, 36% yield for 2 steps). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (1H, s); LC retention time: 2.758 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[NH:6][CH:7]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:17][C:18]1[N:23]=[C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[NH:6][CH:7]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:4]=2)[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Nc1ccccc1-c1nc(C(F)(F)F)c[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1c[nH]c(-c2ccccc2Nc2nc(Cl)ncc2Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
2-(4-Trifluoromethyl-1H-imidazol-2-yl)-phenylamine (0.200 g, 0.880 mmol) and 2,4,5-Trichloro-pyrimidine (0.161 g, 0.880 mmol) were dissolved in N,N-Dimethylformamide (5.0 mL) and the reaction was heated at 50° C. and was allowed to stir overnight. The reaction mixture was poured over saturated ammonium chloride, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 220 mg (67%) of the desired product.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@@H:19]([CH2:24][CH2:25][O:26][CH3:27])[CH2:18]3)[C:14]3[CH:13]=[C:12]([CH2:28]C)[S:11][C:10]=3[NH:9][C:8]=2[CH:30]=1.Cl.[F:32]C1C(F)=CC2N=C(N)C3C=C(C)SC=3NC=2C=1>>[ClH:1].[ClH:1].[F:3][C:4]1[C:5]([F:32])=[CH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@@H:19]([CH2:24][CH2:25][O:26][CH3:27])[CH2:18]3)[C:14]3[CH:13]=[C:12]([CH3:28])[S:11][C:10]=3[NH:9][C:8]=2[CH:30]=1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Reactant: CCc1cc2c(s1)Nc1cc(F)ccc1N=C2N1CCN(C)[C@@H](CCOC)C1
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1C

Procedure:
Using a method similar to the example (S)-6-fluoro 10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2-ethyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride, using 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-methoxy)ethylpiperazine: 1H NMR (DMSO-d6): δ 11.7110 (2H, bs), 9.3793 (1H, bs), 7.3795 (1H, bs), 7.0701 (1H, bt), 6.6326 (1H, bs), 4.1000 (3H, bm), 3.6041 (3H, bs), 3.4347 (3H, bs), 3.2081 (3H, bs), 2.8371 (3H, bs), 2.3319 (3H, bs), 2.2842 (1H, bm), 1.8410 (1H, bs); Mass Spectrum M+H=407.1.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[OH:40].[OH-].[Na+]>C(Cl)Cl.O>[OH:40][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)[CH:38]=[CH:39][C:32]=1[O:31][CH3:30]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C=O)cc1O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/c2ccc(OC)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.3 %

Procedure:
To a stirred mixture of 4-methoxybenzyltriphenylphosphonium chloride (5.51 g, 13mmol) and 4-methoxy-3-hydroxybenzaldehyde (2 g, 13 mmol) in CH2Cl2 was added a cooled aqueous solution of NaOH(62.5 eq) in H2O. The mixture was stirred at room temperature for 48 h. The aqueous layer was then acidified to pH 5 and the precipitated solid was filtered and dried. Purification by silica gel chromatography using hexane/ethyl acetate (1:1) gave the title E-trans product as a colourless solid 0.11 g (3%): 1H NMR (DMSO) δ 9.3 (1H, bs). 7.6 (2H, d), 7.2 (7H, m), 3.5 (6H, s): Mass Spectrum (FAB) 257 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28]Br.BrCC1CCCCO1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: COc1ccc(CBr)cc1OC
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1OC

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 3,4-dimethoxybenzyl bromide (Oguri, T., et al., Chem. Pharm. Bull. (1977), 25:2287-91) to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(3,4-dimethoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one was obtained (100%) as a colorless solid: mp 209-211° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.23-7.14 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.92-6.80 (m, 4H), 6.51 (s, 1H), 6.21 (s, 1H), 5.09 (d, J=15.3 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.68 (d, J=15.3 Hz, 1H), 4.67 (d, J=9.0 Hz, 1H), 4.22-4.16 (m, 2H), 4.13-4.08 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.7, 155.3, 149.5, 148.8, 144.7, 142.2, 138.4, 132.4, 128.9, 128.4, 124.0, 123.5, 121.3, 120.0, 111.5, 111.2, 110.5, 109.5, 99.6, 80.1, 64.6, 64.0, 58.2, 56.02, 55.99, 44.1; MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)=[O:8])[CH2:5][CH2:4]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:11]3[CH:10]=[C:9]([C:7]([NH:6][CH:3]4[CH2:4][CH2:5]4)=[O:8])[CH:13]=[N:12]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(NC1CC1)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sodium hydride (0.98 g, 60%, 25 mmol) was added to a solution of N-cyclopropyl-1H-pyrazole-4-carboxamide (0.49 g, 3.5 mmol) (see following steps B and C for preparation) in 40 mL of THF-DMF (3:1) at 0° C. Stirring for 1 h at 0° C. and 0.5 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.30 g, 3.5 mmol) was added. The reaction mixture was stirred for 2 h at 0° C., quenched with NaHCO3 (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 0.54 g (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.59 (m, 2 H), 0.71-0.79 (m, 2 H), 1.39-1.57 (m, 4 H), 1.60 (s, 9 H), 2.22-2.37 (m, 1 H), 2.71-2.79 (m, 1 H), 3.26-3.34 (m, 2 H), 3.86-3.93 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.91-7.95 (m, 1 H), 7.97-8.01 (m, 1 H), 8.03 (d, J=0.78 Hz, 1 H), 8.34 (d, J=1.37 Hz, 1 H), 8.74 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=485.8.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CCC(=O)O)ccc1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 8.0 g. (0.025 mole) of ethyl 5-(p-chlorobenzoyl)-1-methylpyrrole-2-propionate in 15 ml. ethanol and 30 ml. 1N sodium hydroxide is refluxed for 1 hour. The ethanol is then evaporated and the remaining solution is poured into dilute hydrochloric acid. The resulting white precipitate is filtered off and purified by recrystallization from isopropyl alcohol, 5-(p-chlorobenzoyl)-1-methylpyrrole-2-propionic acid, m.p. 188°-191°C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:20]([O:24][C@@H:25]([C:31]1[C:46]([CH3:47])=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][N:41]=[C:40](Cl)[CH:39]=3)[S:37][C:33]=2[C:32]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([O:24][C@@H:25]([C:31]1[C:46]([CH3:47])=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:7]4[CH:6]=[C:5]5[C:10]([C:2]([F:1])=[N:3][NH:4]5)=[CH:9][CH:8]=4)[CH:39]=3)[S:37][C:33]=2[C:32]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc3c(F)n[nH]c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)n[nH]c5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (prepared according to WO201059658, 48 mg, 0.184 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (75 mg, 0.142 mmol) and 2M potassium carbonate solution (0.28 mL, 0.568 mmol) in dioxane (1.0 mL) was sparged with nitrogen for 10 minutes, Pd(PPh3)4 (16 mg, 0.014 mmol) was added and reaction mixture was heated in microwave at 100° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C34H31ClFN4O3S: 629.2 (M+H+); Found: 629.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:31][CH3:32])=[C:12]([CH:30]=2)[CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]2)[CH:5]=[C:4]([CH3:33])[N:3]=1.[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:14]([CH2:13][C:12]1[CH:30]=[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=2)[CH:9]=[CH:10][C:11]=1[O:31][CH3:32])[CH:15]1[CH2:16][CH2:17][CH:18]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH2:20]1)=[O:41]
Reactant: COc1ccc(-c2cc(C)nc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2cc(C)nc(C)c2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 92 (62 mg, 0.14 mmol) is treated with acid chloride 6 (51 mg, 0.21 mmol) using Method D to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15](OC)=[O:16])[CH3:7].O.[Cl-].[Na+]>C(O)C>[NH2:3][CH2:2][CH2:1][NH:4][C:15]([C:11]1[S:12][CH:13]=[CH:14][C:10]=1[N:9]=[N:8][N:6]([CH3:7])[CH3:5])=[O:16]
Reactant: NCCN
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)N=Nc1ccsc1C(=O)NCCN
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To an ice cold (0-5° C.) solution of ethylenediamine (5 mL) in ethanol (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (250 mg) in ethanol (5 mL) for 5 min and stirred at rt for 24 h. The solution was poured into ice cooled water and saturated with sodium chloride. The solution was extracted with THF (3×100 mL). The combined THF layer was washed with brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (90:10) as eluents to give the product as an off-white solid (60 mg, 22%), mp 98-100° C. 1H NMR (400 MHz, CDCl3): δ 8.65 (1H, br s), 7.30 (1H, d, J=5.2 Hz), 7.28 (1H, d, J=5.2 Hz), 3.50-3.57 (5H, m). 3.24 (3H, br s), 2.91 (2H, t, J=6.0 Hz).