Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[OH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([OH:19])[CH:21]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1cccc(O)c1
Product: O=C(NCc1cccc(O)c1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-hydroxybenzyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.22 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.35 mmol of 3-hydroxybenzylamine. LC/MS [6.01 min; 464 (M+1)]
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22]CC)=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:36][CH3:37])[C:16]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:38]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH:19]([C:20]([OH:22])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:36][CH3:37])[C:16]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)[CH2:11]2)=[O:9])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(OC)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COc2c(OC)ccc3c2CC(C(=O)O)N(C(=O)C(c2ccccc2)c2ccccc2)C3)cc1C

Procedure:
This compound is prepared by a hydrolysis of the ester from Example 34 as follows: a solution of 0.50 g (0.86 mmole) of the ester, 50 mL of methanol, and 2.0 mL of 1N sodium hydroxide is maintained at reflux for 15 minutes. The methanol is removed, water (30 mL) is added, and 1.0 mL of glacial acetic acid is added to precipitate the gummy product. Purification by silica gel chromatography eluting with 5% methanol-chloroform gives pure product; mp 140°-142 ° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]2[C:24]=1[O:23][C:22](=[O:25])[CH:21]=[C:20]2[NH:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])[C:16]([O:35][CH3:36])=[CH:17][CH:18]=2)[O:23][C:22](=[O:25])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CNCCN(C)C
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN(C)CCN(C)C

Procedure:
The title compound was prepared from N1,N1,N2-trimethylethane-1,2-diamine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.23 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.65 (m, 4H), 2.55 (m, 2H), 2.34 (s, 6H), 2.31 (s, 3H), 1.69 (m, 2H), 1.51 (m, 4H); MS (ESI): 523.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[N:20]=[C:21](Br)[C:22]2[N:23]([CH:25]=[CH:26][N:27]=2)[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([NH:17][C:21]3[C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=[C:19]([Br:18])[N:20]=3)[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1cnc2ccc(Nc3nc(Br)cn4ccnc34)cc21

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoimidazole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (3H-Benzoimidazol-5-yl)-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: Cn1cnnc1SCCSc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Cn1cnnc1SCCSc1ccc(N)cc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
4-methyl-3-[[2-[(4-nitrophenyl)thio]ethyl]thio]-1,2,4-triazole (1.4 g) was dissolved in 85% ethanol (42 ml), calcium chloride (0.26 g) and reduced iron (1.32 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[2-[(4-methyl-1,2,4-triazol-3-yl)thio]ethyl]thio]aniline (0.38 g).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O:5]C)=[O:4].Cl>C(O)C>[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1/[CH:18]=[CH:19]/[C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([OH:5])=[O:4]
Reactant: CCCCCC(=O)/C=C/c1scnc1CCCCCCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(=O)/C=C/c1scnc1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.3 %

Procedure:
2 ml of 1 N sodium hydroxide was dropwise added under nitrogen atmosphere and under ice-cooling to a solution of 175 mg of 4-(6-carbomethoxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ia, R1 = H) in 5 ml of ethanol. The solution was subsequently stirred for 1.5 hours at room temperature. Then the reaction mixture was poured onto 30 ml of icewater, acidified with 1 N hydrochloric acid and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was dried over sodium sulphate and evaporated in vacuo. The evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and the organic phase of a mixture of 110 ml of ethyl acetate, 50 ml of n-heptane, 100 ml of water and 20 ml of acetic acid as running solvent. In this way 71 mg of 4-(6-carboxyhexyl)-5-(3-keto-1-trans-octenyl)-thiazole (Ib, R1 = H) of chromatographic purity were obtained. The m.p. and spectroscopical data of the product agreed with those specified in Example 5.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]([C@:16]12[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:19][N:18](CC1C=CC=CC=1)[CH2:17]2)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C@:16]12[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:19][N:18]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[CH2:17]2)=[O:15]
Reactant: COC(=O)[C@]12CCC[C@H]1CN(Cc1ccccc1)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@]12CCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Temperature: 40 °C
Reaction time: 23 h
Yield: 44.9 %

Procedure:
Benzyl chloroformate (3.53 mL, 24.6 mmol) was added to a solution of (1R*,5R*)-3-benzyl-3-azabicyclo[3.3.0]octan-1-ylcarboxylic acid methyl ester (4.27 g, 16.46 mmol) in dichloromethane (50 mL) at room temperature, and the mixture was stirred on an oil bath at 40° C. for 23 hours. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→80:20→67:33) to give 2.24 g (45%) of the title compound as a colorless transparent oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[N:4][NH:5][C:6]=1[C:7]([F:10])([F:9])[F:8].F[C:19]1[CH:34]=[CH:33][C:22]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:21][C:20]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[Cl:1][C:2]1[C:3]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])=[N:4][N:5]([C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:21][C:20]=2[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: CCCN(CCC)c1n[nH]c(C(F)(F)F)c1Cl
Reactant: CCOC(=O)c1cc(C(=O)OCc2ccccc2)ccc1F
Product: CCCN(CCC)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)OCC)c(C(F)(F)F)c1Cl
Yield: 47 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-chloro-N,N-dipropyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (287 mg, 1.06 mmol) and 1-benzyl 3-ethyl 4-fluoroisophthalate (Intermediate 91B, 268 mg, 0.89 mmol) were converted to the title compound (231 mg, 47%). MS(ESI+) m/z 552.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[N:31]12[CH2:39][C:35]([CH2:40][NH2:41])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2>O1CCCC1.CO.C(Cl)Cl>[N:31]12[CH2:39][C:35]([CH2:40][NH:41][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[O:13])([CH2:36][CH2:37][CH2:38]1)[CH2:34][CH2:33][CH2:32]2
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: NCC12CCCN(CCC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCC23CCCN(CCC2)C3)c2ccccc21
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 1-methyl-1-H-indole-3-carboxylic acid (1.53 g, 8.7 mmol) in anhydrous tetrahydrofuran (8 mL) under nitrogen was treated with 1.49 g (9.2 mmol) of 1,1'-carbonyldiimidazole (CDI) and stirred for 10 minutes. At this point a thick suspension formed, and anhydrous N,N-dimethylformamide (8 mL) was added. After an additional 45 minutes the solution was degassed under a stream of nitrogen over 10 minutes, then treated with a solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.47 g, 9.5 mmol). After 18 hours at room temperature and six hours at 55°-60° C., no acid-CDI adduct was detected by TLC (5% methanol/methylene chloride on alumina), and the mixture was concentrated in vacuo. The residue was partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing a little 2-propanol. The organic layer as separated and the aqueous solution was extracted with toluene (50 mL) containing some 2 -propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and the residue filtered through alumina (eluted with 20% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo and the residue triturated from ether/petroleum ethers (30°-60°) to give a solid, which was recrystallized from tetrahydrofuran/hexane to afford 2.06 g (76%) of colorless crystals; mp 145°-147° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCCN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 4-methyl-3-nitrophenol (1.53 g, 10 mmol.), 4-(2-chloroethyl)morpholine (2.79 g, 15 mmol), Cs2CO3 (9.78 g, 30 mmol) and NaI (145 mg, 1 mmol) in DMF (15 mL) was stirred for 3 h at 80° C. The reaction mixture was then cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1:0.05 CH2Cl2/EtOAc/MeOH) to give the title compound as an oil.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]([NH2:20])=[S:19].C(O)C>O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCC(C)C)C(=O)CCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCC(C)C)c1csc(N)n1

Procedure:
Ethyl 2-iso-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 31.9 g.), thiourea (9.72 g.), sodium acetate 3-hydrate (17.4 g.), ethanol (120 ml.) and water (80 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-butoxyiminoacetate (syn isomer, 17.6 l g.), mp 122° to 124° C.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:31])[C@H:12]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH2:44][S:45][CH3:46])[NH:42][C:11](=[O:31])[C@H:12]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CSCC[C@H](N)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 26.6 parts N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester and 12.0 parts L-methionine benzyl ester in 200 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude dipeptide is then subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonyl-L-tryptophyl-L-methionine benzyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCCC(OC)=O)N=2)CC1)=O)(C)(C)C>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: COC(=O)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COC(=O)CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using methyl 4-chlorobutyrate (0.8 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3-methoxycarbonyl-propyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14. found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 4H), 4.07 (t, J=6.6 Hz, 2H), 3.52 (s, 3H), 2.97-2.94 (m, 2H), 2.88-2.84 (m, 4H), 2.70-2.66 (m, 2H), 2.25 (t, J=6.6 Hz, 2H), 1.98-1.95 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(#N)C>[Br:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: BrCCBr
Reactant: NC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1c(O)cccc1OCCBr

Procedure:
A mixture of 23.0 g of 2,6-dihydroxybenzamide, 20.7 g of potassium carbonate and 28.2 g of 1,2-dibromoethane is refluxed, whilst stirring, for 2-3 hours in 300 ml of acetonitrile. The reaction mixture is filtered whilst still warm, the filtrate concentrated by evaporation and the residue recrystallised from a little methanol. 6-(2-Bromoethoxy)salicylamide having a melting point of 120°-121° is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1>>[N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: N#Cc1ccc(Br)cc1
Product: N#Cc1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 330 mg (98% isolated yield) of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:31]3[N:30]=[CH:29][C:28]([CH2:27][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:21](=[O:35])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:33][CH:32]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: COCCN(Cc1ccc(Br)nc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (1) (8.84 g, 52.1 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was warmed to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and 144 (6 g, 17.38 mmol) in THF (25 mL) were added and the mixture was heated to reflux for 1 h. It was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and evaporated under reduce pressure. The residue was purified by flash column chromatography, eluents Hexane/EtOAc:5/5, 3/7, 0/10, to afford compound 145 (5.41 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H). MS (m/z): 434.2 (M+H).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[ClH:36].O1CCOCC1>C1COCC1.C(OCC)C>[ClH:36].[C:1]([NH:4][C@:5]1([C:29]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 2.5 h
Yield: 97 %

Procedure:
While under nitrogen, a stirred solution of tert-butyl (3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-1-carboxylate (400 mg, 0.807 mmol) in anhydrous THF (5 mL) was treated with 4 M HCl in 1,4-dioxane (3.03 mL, 12.1 mmol). After 2.5 h, the mixture was diluted with diethyl ether (15 mL) and filtered, washed with additional ether and concentrated to give (3R,4S)-3acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (340 mg, 97%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.11 (d, J=12 Hz, 1 H), 3.58 (dd, J=11.5, 7.7 Hz, 1 H), 3.19 (d, J=12 Hz, 1 H), 3.01 (t, J=11.5, 1 H), 2.42 (m, 1 H), 1.92 (s, 3 H), 1.52 (m, 1 H), 1.30 (m, 2 H), 1.19 (s, 9 H), 1.16 (s, 12 H), 1.08 (m, 1 H), 0.75 (m, 2 H). LC-MS gives ESI+ MS found for C20H38BN3O4 m/z 396.1 (M+H).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.[ClH:23]>CO>[ClH:23].[NH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(CN)cc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
400 mg of 4′-Aminomethyl-biphenyl-2-sulfonic acid dimethylaminomethyleneamide were treated with 10 ml MeOH and 4 ml conc. HCl and refluxed for 1 h. Solvent and HCl were evaporated and the product used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>>[Cl:8][C:7]1[C:2]2[NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[N:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1c(Cl)cc(Cl)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc(Cl)c2N1
Yield: 15.7 %

Procedure:
Starting from 2-amino-3,5-dichlorobenzenesulfonamide (0.5 g; 2.07 mmol) and isopropyl isothiocyanate (251 mg; 2.48 mmol) with the use of the procedure described in example 4, 100 mg (17.4%) of the title compound was isolated; m.p. >230° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C>O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cnccc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cnccc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 3.40 g of 5-{4-(1-methylimidazo[4,5-c]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 74) and 24 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 1.01 g of the title compound, melting at 264°-265° C.