Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].CCN(CC)CC.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:38]([O:37][C:35]([CH2:34][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH:3]([CH2:2][OH:1])[C:4]([O:6][CH3:7])=[O:5])=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C(CO)C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 5 h
Yield: 71.9 %

Procedure:
The compound of Example 1 (5.65 g, 19.5 mmol) and anhydrous potassium carbonate anhydrous (8 g, 60 mmol) were suspended in DMF (35 mL), a catalytic amount of Et3N was introduced, and ethyl bromoacetate (4.3 mL, 40 mmol) was added dropwise. After stirring for 5 hours, 50 mL of distilled water and 100 mL of ethyl acetate were introduced and stirred to separate layers. The supernatant was washed with a 1N HCl aqueous solution (50 mL), a saturated NaHCO3 aqueous solution (50 mL), and distilled water (100 mL), and it was dried and concentrated under reduced pressure. The mixture was separated using hexane and ethylacetate (2:1) in a silica gel column to obtain a yellow thick oily title compound (5.26 g, yield 72%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH3:29])=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23]([CH3:29])=[N:24][N:25]4[CH3:28])=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a vial was dissolved (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (100 mg, 0.178 mmol) in THF (4 mL) and EtOH (2 mL). 1M NaOH (2 mL) was added, and the mixture was heated to 50° C. overnight. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting with 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C29H29ClN3O3S: 534.1 (M+H+); Found: 534.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.04 (s, 1H), 7.77 (s, 1H), 7.70 (q, J=8.7 Hz, 3H), 7.57 (d, J=6.1 Hz, 3H), 5.25 (s, 1H), 3.98 (s, 3H), 2.59 (s, 3H), 2.51 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=4)[CH2:23][CH2:22]3)[C@@H:17]([CH3:34])[CH2:16]2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[CH3:34][C@H:17]1[CH2:16][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)[CH2:20][CH2:19][N:18]1[CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=2)[CH2:23][CH2:22]1
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(C2(C)CCNCC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 152.9 %

Procedure:
tert-Butyl 4-methyl-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidine-1-carboxylate (0.32 g, 0.6 mmol) was dissolved in a 4 M solution of HCl in dioxane (8.0 mL). After being stirred at room temperature for 2 hrs, the solution was concentrated to give the title compound (0.35 g) as a trihydrochloride salt. MS calculated for C21H30F3N3: (M+H)+382; found 382.2.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].O.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=CC=1.C1(=O)CCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16][C:21]21[CH2:22][CH2:23][CH2:18][CH2:28]2
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C1CCCC1
Product: CN1c2cc(-c3ccncc3)sc2C(=O)NC12CCCC2
Yield: 105.9 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (300 mg, 1.29 mmol), p-toluenesulfonic acid monohydrate (120 mg) and cyclopentan-1-one (10 mL) in toluene (30 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: DCM=1:9) to afford the title compound (200 mg, yield 52%) as an orange solid:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([C:15](=O)[N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3].B#B.Cl>O1CCCC1.O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]2[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN(C)C(=O)c1ccc(-c2csc(NC(=N)N)n2)o1
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1ccc(-c2csc(NC(=N)N)n2)o1
Reaction time: 5 h

Procedure:
To a stirred solution of 676 mg. (2.43 mmole) of 2-guanidino-4-(5-[N,N-dimethylcarbamoyl]-2-furyl)thiazole in 25 ml. of tetrahydrofuran was added dropwise, at room temperature, 24.9 ml. (24.3 mmole) of a 0.97M solution of diborane in tetrahydrofuran. Stirring was continued for 5 hours at room temperature and then 15 ml. of 6N hydrochloric acid was added slowly, keeping the temperature below 30° C. Stirring was continued for 30 minutes, and then the mixture was diluted with water and washed with ethyl acetate. The resulting aqueous phase was made alkaline with 1N sodium hydroxide solution and the solid which precipitated was recovered by filtration, to give 340 mg. of the title compound, mp greater than 200° C.
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:21]([CH:24]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)[CH3:25])=[N+]=[N-].Cl>O1CCCC1.ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:24]([NH2:21])[CH3:25])=[N:27][CH:28]=1
Reactant: CC(N=[N+]=[N-])c1ccc(Cl)cn1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(N)c1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Water (3 mL) and triphenylphosphine (702 mg) were added to a solution of 2-(1-azidoethyl)-5-chloropyridine (333 mg) in tetrahydrofuran (10 mL), and the reaction solution was stirred at 60° C. for two hours. The reaction solution was returned to room temperature. Dichloromethane and 5 N hydrochloric acid were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was made basic (pH 14) with a 5 N sodium hydroxide solution. Then, dichloromethane was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 260 mg of the title compound.
Reaction SMILES: Br.Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:21])[N:15]([CH2:16][C:17]([F:20])([CH3:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:22]>CO>[F:20][C:17]([CH3:19])([CH3:18])[CH2:16][N:15]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:22])[C:12]=2[N:13]=[C:14]1[NH2:21]
Reactant: CC(C)(F)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: CC(C)(F)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
Crude 4-chloro-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide (1.14 g) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. for five days. Additional ammonia in methanol was added after three days and again after four days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was combined with material from another run. The crude product was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 1:14:85) to provide 270 mg of 1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2,4-diamine as a light tan solid, mp 251° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[CH:20]=[N:21][CH:22]=[C:18]3[CH2:17][N:16]([CH3:23])[C:15](=[O:24])[C:14]=2[CH:25]=1.O>CN(C)C=O>[Br:1][C:22]1[N:21]=[CH:20][N:19]2[C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:25][C:14]=3[C:15](=[O:24])[N:16]([CH3:23])[CH2:17][C:18]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(Br)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.58 g of N-bromosuccinimide are added to 4.62 g (20 mmol) of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 100 ml of dimethylformamide and the mixture is stirred at room temperature for 2 hours. Subsequently, the mixture is poured into 500 ml of water and extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there is obtained 3-bromo-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 200°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[CH2:15]([O:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](Cl)=O)=[CH:20][CH:19]=1)[CH3:16].N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54]>C(OCC)(=O)C>[C:52]([OH:57])(=[O:56])[C:53]([OH:55])=[O:54].[O:17]([C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=2)=[CH:20][CH:19]=1)[CH2:15][CH3:16]
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: CCOc1ccc(C=CC(=O)Cl)cc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(/C=C/c2nc3ccccc3n2-c2ccccn2)cc1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 4-ethoxycinnamoyl chloride (Lohar, J. M.; Mahsru, U. Indian J. Chem. Sect. A, 1981, 20, 125) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 431.45; mp: 169.0-170.0° C.; 1H-NMR (DMSO) δ: 8.78 (1H, dd, J=5.1, 1.4 Hz), 8.18 (1H, td, J=7.7, 1.8 Hz), 7.85 (1H, d, J=16.1 Hz), 7.73 (2H, t, J=6.8 Hz), 7.67-7.61 (1H, m), 7.55 (2H, d, J=8.8 Hz), 7.43 (1H, d, J=7.7 Hz), 7.35-7.22 (2H, m), 7.01 (1H, d, J=16.1 Hz), 6.94 (2H, d, J=8.8 Hz), 4.06 (2H, q, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:38])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:29]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(CCc3ccccc3)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(CCc2ccccc2)cc1)C(=O)O
Reaction time: 3 h

Procedure:
5.15 g (10.31 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2-phenylethyl)phenyl]methyl}dihydrofuran-2-(3H)-one in 166 ml of dimethoxyethane and 85 ml of water are hydrolysed, under protective gas, with 41 ml of a 1M lithium hydroxide solution. After 3 h, the dimethoxyethane is evaporated off on an RE, and the residue is treated with an ice-cold mixture of 506 ml of sat. NH4Cl solution, 42 ml of 10% citric acid solution and 207 ml of methylene chloride. Methanol is added to dissolve the product completely. The aqueous phase is separated off and extracted 2× with methylene chloride/methanol, 10:1. The organic phases are washed with saline, dried with Na2SO4 and evaporated: tRet (II)=17.8 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])C1C=C(C2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)C=CC=1.C(N)C#C.C([C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:45][N:44]([C:46]([NH:48][CH2:49][CH:50]=[CH2:51])=[O:47])[CH2:43]2)=[CH:38][CH:37]=1)(C)(C)C>>[F:1][C:2]([F:27])([F:26])[C:41]1[CH:40]=[C:39]([CH:42]2[CH2:43][N:44]([C:46]([NH:48][CH2:49][C:50]#[CH:51])=[O:47])[CH2:45]2)[CH:38]=[CH:37][CH:36]=1
Reactant: C=CCNC(=O)N1CC(c2ccc(C(C)(C)C)cc2)C1
Reactant: FC(F)(F)c1cccc(C2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: C#CCN
Product: C#CCNC(=O)N1CC(c2cccc(C(F)(F)F)c2)C1

Procedure:
This product was prepared from compound (38) and propargylamine using the procedure described for compound (12). m.p. 121° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6]C1=O)([CH3:3])[CH3:2].[OH-].[K+].Cl.[OH-].[Na+]>O.CCOCC.O1CCOCC1>[OH:6][C:7]1([CH2:8][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)NCC1(O)COc2ccc([N+](=O)[O-])cc2OC1

Procedure:
A mixture of 3'-isopropyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidin-2'-one (7.98 g.; 25.9 mmole), dioxane (60 ml. and 45% aqueous potassium hydroxide solution (16 ml.) in a nitrogen-filled steel pressure-vessel is heated in a rocking-furnace at 150°-160° C. for 16 hours. The reaction mixture then is poured into ether (100 ml.) and the organic layer separated. The aqueous solution is extracted with ether (100 ml.) and the combined ethereal solution is washed twice with saturated sodium chloride solution (2 × 100 ml.) and then with water (100 ml.). The ethereal solution is extracted with 2.75N hydrochloric acid (40 ml.; 0.11 mole) and twice with water (2 × 40 ml.). The combined acid and aqueous extracts is basified with 2.5N sodium hydroxide solution (70 ml.; 0.175 mole) and the liberated base extracted with ether (2 × 100 ml.). After drying the ethereal solution over anhydrous magnesium sulfate and then over calcium sulfate mixed with a little charcoal, it is evaporated to an oil that soon crystallizes providing 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin as a bright yellow solid, yield 6.33 g., (86.7%), m.p. 95-96.5` C. Recrystallization from di-isopropyl ether (63 ml.) affords 4.56 g., (62.4%) of product, m.p. 97.5°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[N:9](C(OC(C)(C)C)=O)[CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cn(C(=O)OC(C)(C)C)c2cnc(-n3cncn3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cncn3)cc12
Yield: 82.4 %

Procedure:
A solution of ethyl-3-[1-tert-butyloxycarbonyl-5-(1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-3-yl]prop-2-enoate (1.73 g, 4.5 mmol) and trifluoroacetic acid (5 mL) in dry DCM (20 mL) was stirred at ambient temperature under nitrogen for 5 hours. The solvent was evaporated in vacuo and the residue azeotroped with toluene. The residue was chromatographed on silica eluting with 20% EtOAc in DCM followed by a gradient of 5 to 10% MeOH in DCM to give a colourless solid. This was triturated with ether to give the title compound (1.05 g, 82%) as a colourless solid. mp 235°-238° C. 1H NMR (360 MHz, d6 -DMSO) δ 1.29 (3H, t, J=7.1Hz), 4.20 (2H, q, J=7.1Hz), 6.44 (1H, d, J=16.0Hz), 7.92 (1H, d, J=16.1Hz), 8.22 (1H, s), 8.27 (1H, s), 8.33 (1H, d, J=2.7Hz), 8.76 (1H, s), 9.31 (1H, s) and 12.46 (1H, br s).
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)([O:3][CH3:4])=[O:2].N1C=CC=CC=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[C:1]([O:3][CH3:4])=[O:2])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: COC(=O)C1CCCN1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C1CCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
To 2-carbomethoxypyrrolidine (d,1-proline methylester, 1.64 g, 12.7 mmol) with pyridine (10.1 g, 12.7 mmol) in CH2Cl2 (100 mL) at 0° C. was added 4-nitrobenzoyl chloride (2.36 g, 12.7 mmol) in CH2Cl2 (25 mL) dropwise. The reaction was allowed to warm to ambient temperature and stirred 18 h. The reaction was evaporated and applied to a silica gel flash column and eluted with a gradient of 2:1 Hexane:EtOAc to 1:2 Hexane:EtOAc. There was isolated 1.3 g of the title compound; LRMS (M+H)+ m/z=279.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29](B(O)O)[CH:30]=2)[CH:25]=[CH:24]1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[C:31]4[C:26]([CH:25]=[CH:24][NH:23]4)=[CH:27][CH:28]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3ccc4cc[nH]c4c3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and 1H-indol-6-ylboronic acid according to the procedure described in example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][C:9]=1N)([O-:3])=[O:2].OS(O)(=O)=O.N([O-])=O.[Na+].[S-:22][C:23]#[N:24].[K+]>O.[Co](Cl)Cl>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][C:9]([S:22][C:23]#[N:24])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl[Co]Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(SC#N)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A sample of 3-nitro-4-aminoanisole (13.5 g, 80 mmol) was dissolved in water (100 mL) and concentrated H2SO4 (44 mL), cooled to 0° C., and diazotized with a solution of sodium nitrite (14.3 g, 207.2 mmol) in water (25 mL) while maintaining a temperature no greater than 5° C. The resulting solution was added dropwise with vigorous stirring to a solution of crystalline cobalt chloride (42 g, 176 mmol) and potassium thiocyanate (25.6 g, 264 mmol) in water (100 mL), after which the mixture was stirred at 0-10° C. for 3 h and allowed to stand overnight. It was then stirred at 50° C. for 16 h until nitrogen evolution had ceased. The precipitate was removed by filtration, washed with water, and dried at 80° C. to give 4-methoxy-2-nitro-1-thiocyanatobenzene (intermediate 22) (9.82 g, 58%). mp: 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][OH:30])=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: N[C@@H](CO)c1ccccc1
Product: O=C(N[C@@H](CO)c1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (R)-2-amino-2-phenylethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield (R)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxy-1-phenylethyl)terephthalamide. MS (Q1) 506 (M)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:30])[NH:14][C:15]1[CH:16]=[C:17]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:19]3=[C:20](Cl)[NH:21][C:22]([CH:23]=1)=[C:18]23)([CH3:11])([CH3:10])[CH3:9].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O)CCC>CO>[C:8]([O:12][C:13](=[O:30])[NH:14][C:15]1[CH:16]=[C:17]2[C:28](=[O:29])[NH:27][N:26]=[CH:25][C:19]3=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[NH:21][C:22]([CH:23]=1)=[C:18]23)([CH3:11])([CH3:10])[CH3:9]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc2c3c(c(Cl)[nH]c3c1)C=NNC2=O
Solvent: CCCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(N4CCOCC4)[nH]c3c1)C=NNC2=O
Yield: 22.9 %

Procedure:
Triethylamine (0.039 mL, 0.28 mmol), the title compound of Example 187 (46 mg, 0.14 mmol), morpholine (96 mg, 1.1 mmol) and n-butanol (5 mL) were stirred in a flask with a condenser at 120° C. overnight. The mixture was allowed to stand at room temperature for two more days. The volatile components were removed under vacuum and the resulting mixture was subjected to silica gel chromatography, eluting with 95:5 dichloromethane:methanol to afford the title compound (12.5 mg, 0.032 mmol) as a yellow solid in 23% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:13]1[CH:18]=[C:17]([F:19])[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([F:28])[CH:14]=1.[OH-:29].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[F:19][C:17]1[CH:18]=[C:13]([N:6]2[C:7]3[C:3](=[C:2]([OH:29])[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=3)[CH:4]=[N:5]2)[CH:14]=[C:15]([F:28])[C:16]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1cc(Br)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cc(O)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Temperature: 90 °C
Yield: 76.6 %

Procedure:
To a solution of 4-bromo-1-{3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}-1H-indazole-6-carbonitrile (D36) (940 mg, 2.135 mmol) in dioxane (20 mL) and water (20 mL) was added potassium hydroxide (479 mg, 8.54 mmol). The mixture was degassed with argon and then treated with 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (54.4 mg, 0.128 mmol) and tris(dibenzylideneacetone)dipalladium(0) (39.1 mg, 0.043 mmol). The reaction mixture was heated to 90° C. for 1 hour. The reaction was diluted with ethyl acetate and water. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to give the title compound (D37) (617 mg).