Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13]I>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C#N)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 54.9 %

Procedure:
To a solution of 3-bromophenylacetonitrile (12 g, 61.2 mmol) in tetrahydrofuran (150 ml) cooled down to 0° C., was added 60% sodium hydride in mineral oil (2.25 g, 56.3 mmol) portionwise over 10 minutes. The reaction mixture was stirred at 0° C. for 40 minutes. Methyl iodide (5.71 ml, 91.8 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for a further 1 hour. The reaction mixture was diluted with ethyl acetate (250 ml), washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion, 330 g column, 0-20% EtOAc/Petrol) to afford the title compound as a colourless oil (7.06 g, 55% yield).
Reaction SMILES: O.[F:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6](=[O:11])[NH:5][CH:4]=1.OO.S(=O)(=O)(O)[OH:15]>[OH-].[Na+]>[F:2][C:3]1[N:8]=[C:7]([C:9]([NH2:10])=[O:15])[C:6]([OH:11])=[N:5][CH:4]=1
Reactant: N#Cc1nc(F)c[nH]c1=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
At a water-cooled temperature, 2.2 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was dissolved in an aqueous solution of sodium hydroxide prepared from 1.27 g of sodium hydroxide and 24.2 ml of water. After adding 2.75 ml of 30% hydrogen peroxide at the same temperature as above, the mixture thus formed was stirred at 40° C. for 1.5 hours. After dropwise adding 2.77 mL of concentrated sulfuric acid to the reaction mixture obtained above while cooling it with ice, the mixture thus formed was cooled to 10° C. The deposited crystalline product was collected by filtration and washed with 2 mL of cold water to obtain 2.2 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a light yellow-colored solid product.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:5](=[O:12])[NH:4][NH:3]1.[CH3:13]O.Cl>O1CCOCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][C:5](=[O:12])[NH:4][NH:3]1
Reactant: CO
Reactant: O=C(O)Cc1cc(=O)[nH][nH]c1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(=O)[nH][nH]c1=O
Reaction time: 8 h

Procedure:
A mixture of (3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)acetic acid, (5.0 g), methanol (75 ml) and 4M hydrochloric acid in 1,4-dioxane (20 ml) was stirred overnight. Evaporation afforded a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][C:39]([F:42])([F:41])[F:40])[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O.ClC(OCC)=O.C(N(CC)CC)C>>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][C:39]([F:42])([F:41])[F:40])[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1
Agent: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a flask containing (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.249 mmol) was added trifluoroacetic acid (5 mL). When all the starting material was consumed, as indicated by TLC, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane (10 mL) and then cooled to 0° C. Ethyl chloroformate (24 μL, 0.249 mmol) and triethylamine (75.5 mg, 0.747 mmol) were added dropwise, and the reaction mixture was stirred for 2 h at room temperature and then concentrated. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution with 0%-100% ethyl acetate in hexane) to give (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (61 mg, 42.7% yield) as a light yellow solid. LCMS for C24H21F6N5O5 calculated (m/e) 573.46, found 574.15 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([Cl:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.O.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[Cl:17][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1c(Cl)nc2cccnc2c1Cl
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(-c2cccc(F)c2)nc2cccnc2c1Cl
Temperature: 25 °C

Procedure:
To a stirred suspension of ethyl 2,4-dichloro-1,5-naphthyridine-3-carboxylate (1.0 g, 3.69 mmol) in acetonitrile:water (7 mL:2 mL) was added Pd (PPh3)4 (0.426 g, 0.369 mmol), 3-fluorophenylboronic acid (0.568 g, 4.06 mmol) and sodium carbonate (0.782 g, 7.38 mmol) and the reaction was heated at reflux for 6 h. After this time the reaction was cooled to rt and partitioned between EtOAc (80 mL) and water (30 mL). The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The mixture was purified by column chromatography on silica gel using a gradient from 1:0 to 4:1 of hexane:EtOAc to give ethyl 4-chloro-2-(3-fluorophenyl)-1,5-naphthyridine-3-carboxylate as a white solid: LC-MS (ESI) m/z 331.0 [M+H]+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:4]3[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=3[Cl:2])[N:13]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Br
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2cc([N+](=O)[O-])ccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-amine hydrobromide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (16.5 mg) with purity >90%. 1H-NMR (DMSO-d6) δ 13.43 (s, NH), 8.46 (d, J=2.8 Hz, 1 H), 8.29 (d, J=2.8 Hz, 1 H), 7.96 (dd, J=1.1 Hz, J=8.0 Hz, 1 H), 7.90 (d, J=8.8 Hz, 1 H), 7.70 (dd, J=1.1 hz, J=8.0 Hz, 1 H), 7.42 (t, J=8.0 Hz, 1 H), 7.52 (s, 1 H), 2.67 (s, 3 H); MS (pos) m/z 442.2,444.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (764 mg, 3.0 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (710 mg, 3.0 mmol) and DIPEA (2.6 mL, 15 mmol) in IPA (8 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in EtOAc) to afford 210 as a white solid (700 mg, 63%). LCMS (Method K): RT 2.94 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, br s), 8.61 (1H, br s), 8.20-7.80 (4H, m), 7.79-7.67 (2H, m), 7.52-7.43 (1H, m), 7.20-7.08 (2H, m), 5.86 (1H, br s), 1.63 (3H, d, J=6.82 Hz)
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:11]([CH3:12])=[CH:10][S:9][CH:8]=1.CN([CH:16]=[O:17])C.Cl>CCOCC.C1COCC1>[CH:16]([C:8]1[S:9][CH:10]=[C:11]([CH3:12])[C:7]=1[CH3:6])=[O:17]
Reactant: Cc1cscc1C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1csc(C=O)c1C
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution of 1.5 M n-butyllithium (3.4 mL, 5.1 mmol) in ether was added dropwise under argon to a solution of 3,4-dimethylthiophene trimer (1.62 g, 4.8 mmol, See Example 16) in dry THF (10 mL) at −70° C. and the resultant solution was warmed to −50° C. Next, 0.4 mL (5.4 mmol) of DMF was added dropwise and the mixture allowed to warm to room temperature overnight. The mixture was poured into a mixture of 1 liter of 12 M HCl and crushed in certain embodiments and thereafter extracted with ether. The organic layers were combined, washed with water, and dried over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography (silica gel, hexane/CH2Cl2 (v:v) 3:1) to give the product 2-formyl-3,4-dimethylthiophene as a yellow solid (0.98 g, 56%) and recovered unreacted trimer (0.55 g). 1H NMR (CDCl3) δ 10.08 (1H, s, CHO), 6.99 (1H, s, aromatic H), 2.53 (3H, s, CH3), 2.22 (3H, s, CH3), 2.16 (3H, s, CH3), 2.13 (3H, s, CH3), 2.10 (6H, s CH3).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6](C(OC(C)CC)=O)[C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:4][CH2:3]1.Cl[C:33]1[C:42]2[CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][CH2:38][C:37]=2[N:36]=[C:35]([CH3:45])[N:34]=1>>[CH:2]1([C:5]2[NH:6][C:7]3[C:8]([N:24]=2)=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:33]5[C:42]6[CH2:41][C:40]([CH3:43])([CH3:44])[CH2:39][CH2:38][C:37]=6[N:36]=[C:35]([CH3:45])[N:34]=5)[CH2:18][C:17]=4[CH:23]=2)[CH:12]=3)[CH2:3][CH2:4]1
Reactant: CCC(C)OC(=O)n1c(C2CC2)nc2ncc(-c3ccc4c(c3)CNCCO4)cc21
Reactant: Cc1nc(Cl)c2c(n1)CCC(C)(C)C2
Agent: Cl
Product: Cc1nc2c(c(N3CCOc4ccc(-c5cnc6nc(C7CC7)[nH]c6c5)cc4C3)n1)CC(C)(C)CC2

Procedure:
Prepared according to the method of example 6 by using 1-methylpropyl 2-cyclopropyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (reagent preparation 19) and 4-chloro-2,6,6-trimethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 8) in step 3. 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.98 (s, 1H), 7.61 (d, 1H), 7.49 (dd, 1H), 7.09 (d, 1H), 4.71 (s, 2H), 4.32 (m, 2H), 3.97 (m, 2H), 2.75 (t, 2H), 2.46 (s, 2H), 2.40 (s, 3H), 2.21 (m, 1H), 1.66 (t, 2H), 1.22 (m, 4H), 0.91 (s, 6H); MS (EI) for C29H32N6O: 481 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.O[N:52]1C2C=CC=CC=2N=N1.N>C1COCC1.[Pd]>[OH:1][C:2]1[C:7]2[C:8]3([OH:45])[C:21]([O:25][CH3:26])([CH:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH2:52])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[CH:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COC1[C@@H](NC2=CC(=O)c3c(cc4c(c3O)C(=O)C3(OC)C(O)Cc5cc(C)c(C(N)=O)c(O)c5C3(O)C4=O)C2=O)O[C@@H](C)[C@H](OC)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (100 mg, 0.15 mmol) in THF (2 mL) was added 10% Pd/C and the reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere for 4 h. The reaction mixture was filtered without exposure to air into another flask containing polystyrene-carbodiimide (260 mg, 0.29 mmol) and the mixture was stirred for 10 min. A solution of 1-hydroxybenzotriazole hydrate (40 mg, 22 mmol) in THF (1 mL) and ammonia (0.22 mL, 2.0 M solution in THF, 0.16 mmol) were added and the reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) to afford 6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((2S,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (12 mg, 15%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.19 (s, 1H), 12.89 (s, 1H), 8.22 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.52 (s, 1H), 5.96 (s, 2H), 5.87 (s, 1H), 4.96 (d, J=6.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 3.79 (s, 3H), 3.78-3.66 (m, 3H), 3.61 (s, 3H), 3.59-3.50 (m, 2H), 3.40 (s, 3H), 3.37-3.30 (m, 3H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (s, 3H), 1.36 (s, 3H); MS (ESI+) m/z 683 (M+H); HPLC 94.3% (AUC), tR 11.64 min.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(C(CCCCl)=NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-methylbutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.15 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 8.65 g (64%) of the tide compound as an off-white solid, mp133-135° C.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Br:19])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2cccc(C)c2)c1
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(-c2cccc(CBr)c2)c1

Procedure:
3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 3′-Methyl-biphenyl-3-carboxylic acid ethyl ester (4.2 g, 17.48 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.73 g, 20.98 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.14 g, 0.87 mmol, 5 mol %). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:7]([CH:20]=1)[C:8]([N:10](CC)[CH:11](OC)[C:12](C)(C)C)=[O:9].I[Si](C)(C)C>ClCl>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:23])([CH3:22])[CH3:24])=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH3:12])=[O:9]
Reactant: CCN(C(=O)c1cc(N(C)C)ccc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: C[Si](C)(C)I
Agent: ClCl
Product: CCNC(=O)c1cc(N(C)C)ccc1[Si](C)(C)C
Reaction time: 2 h

Procedure:
The compound of Example 222 (0.31 g, 0.85 mmol) was dissolved in CH2 Cl2 (20 mL) and was treated with iodotrimethylsilane (2.1 mL, 15 mmol) in a foil-covered flask. The reaction was stirred for 2 h and was quenched with sat NaHCO3. The mixture was extracted with ether, the organic layers were washed with brine and sat sodium bisulf ite, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallized from hexanes to afford 68 mg (5%) of the title compound as a white solid. m.p. 141°-143° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>ClCCl.N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:25]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2(C#Cc3cccc(N)c3)CCC(=O)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-1-one (0.07 g, 0.18 mmol) in dichloromethane (2 mL) under an argon atmosphere. were added pyridine (three drops) and acetic anhydride (0.05 mL, 0.53 mmol) and the reaction was stirred at room temperature for 2 h. Hydrochloric acid (1N) was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)cyclohexanone as a white solid. mp 63°-64° C.; Anal. (C28H31NO4.1.75 H2O) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([NH:23]S(C(C)(C)C)=O)[CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C([O-])(O)=O.[Na+]>CO.O>[NH2:23][CH:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[CH:10]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)NC(c1cccc(C#N)c1)C(c1cccnc1)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cccc(C(N)C(c2cccnc2)c2cccnc2)c1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
N-[1-(3-cyanophenyl)-2,2-dipyridin-3-ylethyl]-2-methylpropane-2-sulfinamide (Diastereomer B, 1.567 g, 3.87 mmol) was dissolved in CH3OH (15 mL) and the solution was cooled to 0° C. HCl (4 M solution in dioxane, 2.905 mL, 11.62 mmol) was added drop-wise. The reaction was allowed to warm to RT and was stirred for 7 hr. The reaction was diluted with H2O and the pH was adjusted to pH=7 using saturated aqueous NaHCO3. The product was extracted with ethyl acetate (3×75 mL) followed by isobutanol (6×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford 3-(1-amino-2,2-dipyridin-3-ylethyl)benzonitrile as a foamy light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](/[CH:13]=[CH:14]/[N:15](C)C)=[C:4]([N+]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(OCC)(=O)C.[H][H]>[Ni].O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:15][CH:14]=[CH:13][C:3]=12
Reactant: COc1ncc(Br)c(/C=C/N(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(Br)c2cc[nH]c12
Yield: 56 %

Procedure:
(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added to Ra-Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) in a stainless steel pressure bottle and stirred for 30 minutes at 30 psi of hydrogen and room temperature. The reaction mixture was filtered, and concentrated. The residue was triturated with dichloromethane, and the solid collected by filtration to provide 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (5.82 g). The mother liquor was evaporated and the residue triturated again with dichloromethane and filtered to provide an additional 1.63 g of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine. Total yield=7.45 g, 72% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[Sn](Cl)Cl.N>C(O)C.Cl.O>[NH2:16][C:15]1[C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N)c2s1
Temperature: 80 °C
Yield: 162.2 %

Procedure:
A stirred suspension of 1-Ethyl-3-(7-nitro-5-pyridin-3-yl-benzothiazol-2-yl)-urea (25 mg, 0.0728 mmol) in ethanol (0.5 ml) and concentrated hydrochloric acid (0.5 ml) was treated with tin (II) chloride (69 mg, 0.364 mmol) and heated at 80° C. for 5 h. After cooling to ambient temperature, the mixture was diluted with water (50 ml) and made alkaline (pH 11) by the addition of concentrated ammonia. The 1-(7-Amino-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea was extracted with ethyl acetate (3×50 ml) which was dried (MgSO4) and the solvent removed in vacuo to give an off-white solid (37 mg) which was used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:24]1[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][N:29]=1>O.COCCOC.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>[CH:7]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][N:29]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OB(O)c1ccc(OC2CCCCC2)cc1
Reactant: Nc1nccnc1Cl
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nccnc1-c1ccc(OC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
A mixture of sodium carbonate (491 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), 4-(cyclohexyloxy)phenylboronic acid (612 mg) and 3-chloropyrazin-2-amine (300 mg) in water (3 mL) and DME (15 mL) was stirred at 80° C. for 4 hr. Silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give 3-[4-(cyclohexyloxy)phenyl]pyrazin-2-amine (485 mg) as a white solid.