Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[CH:16][C:15]=2[F:24])[C:10]([CH3:27])([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3OC=CC=3C(F)=CC=2F)C(C)(C)C1)C1C=CC=CC=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([F:23])=[CH:16][C:15]=2[F:24])[C:10]([CH3:27])([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1(O)c1c(F)cc(F)c2ccoc12
Agent: CC(=O)C(=O)OC1(c2c(F)cc(F)c3ccoc23)CCN(Cc2ccccc2)CC1(C)C
Agent: CCCC[SnH](CCCC)CCCC
Product: CC1(C)CN(Cc2ccccc2)CCC1c1c(F)cc(F)c2ccoc12
Yield: 43.6 %

Procedure:
Beginning with 0.84 gm (2.26 mMol) 1-benzyl-3,3-dimethyl-4-hydroxy-4-(4,6-difluorobenzofur-7-yl)piperidine, 0.84 gm (81%) 1-benzyl-3,3-dimethyl-4-(methyl oxoacetoxy)-4-(4,6-difluorobenzofur-7-yl)piperidine were prepared essentially as described in EXAMPLE 16. This material (0.57 gm, 1.25 mMol) was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to prepare 0.35 gm (79%) of the desired compound.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([F:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2].[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:11][C:10]([F:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(F)cc(Cl)c2[nH]c1=O
Reactant: CC(C)CCN
Product: CC(=O)c1c(NCCC(C)C)c2cc(F)cc(Cl)c2[nH]c1=O
Yield: 85.9 %

Procedure:
3-Acetyl-8-chloro-6-fluoro-4-methylsulfoxy-2-quinolinone (3.02g, 0.01 mol) and isoamylamine (0.87g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.79g, yield: 86% ).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])C.[Li+].[OH-].Cl>O1CCCC1>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([C:13]2[CH:12]=[N:11][C:10]3[N:9]([N:8]=[CH:7][C:6]=3[C:4]([OH:5])=[O:3])[C:14]=2[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:22][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(Cc4ccccc4)cc3)cnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn2c(C3CCCCC3)c(-c3ccc(Cc4ccccc4)cc3)cnc12
Yield: 20.7 %

Procedure:
To a solution of 36 mg (0.082 mmol) of 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester in 3 mL of tetrahydrofuran was added 0.5 mL (0.5 mmol) of 1 M LiOH solution, and the resulting mixture was heated at reflux overnight. The reaction mixture was then acidified with 1 M HCl solution to pH=2, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and concentrated to give a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 7 mg (21% yield) of 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as a solid (90% purity, entry 444) as indicated by 1H NMR; LC-MS—calcd for C26H25N3O2 [M++H]+: 412.19, found: 412.3.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccccc12
Reaction time: 6 h
Yield: 94 %

Procedure:
A mixture of 52.35 g (368.1 mmol) of 1-methylnaphthalene, 68.79 g (368.5 mmol) of N-bromosuccinimide (NBS), 0.45 g (1.86 mmol) of benzoyl peroxide (BPO) and 250 ml of carbon tetrachloride was stirred for 6 hours while heating and refluxing. The deposit was removed by filtration, and the filtrate was concentrated to obtain 84.64 g (purity: 90.4%, yield: 94%) of an oily crude product of 1-(bromomethyl)naphthalene.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[N:10][C:9]=1[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3cccc(OC)c3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1cccc(O)c1
Yield: 65 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-3-methyoxy-benzamide prepared in Example 42 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 65.0%, mp: 233-234 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.23 (2H, s, CH2), 6.83 (2H, d, J=7.28 Hz, ArH), 6.98˜7.02 (1H, m, ArH), 7.22˜7.35 (6H, m, ArH), 7.40 (1H, s, ArH), 7.46 (2H, d, J=7.28 Hz, ArH), 7.52 (1H, d, J=7.56 Hz, ArH), 9.50 (1H, br, OH), 12.50 (1H, br, CONH); EI-MS m/e (%): 402.1 (M+, 83), 121.0 (100); HREI-MS Calcd. for C23H18N2O3S: 402.1038, found: 402.1042.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([Br:14])=[C:6]([OH:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][C:3]1=2.[CH3:20][O:21][CH2:22]Cl.C(N(C(C)C)CC)(C)C.[Br-]>C(Cl)Cl>[Br:14][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:19])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]=1[O:15][CH2:20][O:21][CH3:22]
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Reactant: COCCl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) and a catalytic amount of tetrabutylammouimn bromide. The reaction mixture was heated to 45° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the methoxymethyl ester of the title compound as a white solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of NaOH (0.5 ml, 1M) was added. The reaction mixture was stirred at room temperature for over night. The EtOH was removed and the residue was added 2 ml of ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HCl to PH=7. The ethyl acetate layer was separated and washed with brine, dried over Na2SO4. After filtration of the drying agent and removal of solvent, the reaction yielded the title compound as a white solid (155 mg). 1H NMR d 7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[C:24]([Cl:37])=[C:25]([CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:26]=[N:27][CH:28]=1>>[Cl:37][C:24]1[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)=[CH:28][N:27]=[CH:26][C:25]=1[CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]
Reactant: CC(C)(C)[S@@](=O)NCc1cncc(Br)c1Cl
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(CN[S@](=O)C(C)(C)C)c3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to (R)—N-((5-bromo-4-chloropyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (intermediate A-58) to give the title compound as an orange solid. MS: 406.4 (M+H+).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:17]([O-:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])([C:2]([OH:1])([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[CH3:20]
Reactant: CCOC(=O)C(=O)CCNc1cccnc1
Reactant: CCOP([O-])OCC
Product: CCOC(=O)C(O)(CCNc1cccnc1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 3.36 g (0.01 mole) of ethyl 2-oxo-4-(3-pyridylamino)butanoate in 6.9 g (0.05 mole) of diethyl phosphite is stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chloroform/ethanol as eluant.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CO.C(OCC)(=O)C>[OH:3][C:2]1[CH2:4][O:5][C:6](=[O:7])[C:1]=1[C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C:36]#[C:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: CCCCCCCCC#CCCCCCCCC(=O)O
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCC#CCCCCCCCC(=O)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a stirring solution of 1.62 g (17.86 mmol) of tetronic acid in 50 mL of dimethylformamide is added 2.5 mL (17.86 mmol) of triethylamine and 652 mg of 4-dimethylaminopyridine at 0° C. Next, 3.71 g (19.35 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.0 g (17.86 mmol) of stearolic acid are added and the reaction is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted with three 50 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material was obtained by flash chromatography with 10% methanol/ethyl acetate as eluant affording 3.3 g (56%) of 4-hydroxy-3-(1-oxo-9-octadecynyl)-2(5H)-furanone.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[N:5][N:6]=1.[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11]>>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: NCCCN
Reactant: Brc1nncs1
Product: NCCCNc1nncs1

Procedure:
By the procedure of Example 188, 2-bromo-1,3,4-thiadiazole is reacted with 1,3-diaminopropane to give 2-(3-aminopropylamino)-1,3,4-thiadiazole and this intermediate is reacted with methyl isothiocyanate to give N-methyl-N'-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]thiourea.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[N:14]1([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[CH:18]=[CH:17][N:16]=[N:15]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(=O)(O)[O-].[Na+].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]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([N:14]2[CH:18]=[CH:17][N:16]=[N:15]2)[N:24]=1)=[O:5])[CH3:2]
Reactant: Nc1cccc(-n2ccnn2)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Temperature: 100 °C
Yield: 15.3 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (200 mg, 0.905 mmol) and 6-[1,2,3]triazol-1-yl-pyridin-2-ylamine (147 mg, 0.914 mmol) were dissolved in 1,4-dioxane (6 mL) and the solution was purged with argon. Tris(dibenzylideneacetone)dipalladium (83 mg, 0.09 mmol), Xantphos (105 mg, 0.18 mmol), and cesium carbonate (884 mg, 2.7 mmol) were added and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica, 25 to 100% ethyl acetate in hexanes) gave 6-chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (48 mg, 15%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 9.34-9.43 (m, 1H) 8.54-8.57 (m, 1H) 8.43 (d, J=1.1 Hz, 1H) 7.87-7.97 (m, 3H) 7.60 (dd, J=7.4, 1.3 Hz, 1H) 4.55 (q, J=7.2 Hz, 2H) 1.50 (t, J=7.2 Hz, 3H); MS (EI/CI) m/z: 346 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:15](=[O:16])[CH2:14][CH:13]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:1][C:2]4[N:7]=[CH:6][C:5]([N:8]5[C:15](=[O:16])[CH2:14][CH:13]6[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:11][CH2:12]6)[CH2:9]5)=[CH:4][CH:3]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCC1
Yield: 55.2 %

Procedure:
Following general N—C coupling procedure 1, tert-butyl 3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (120 mg, 0.361 mmol) was combined with 2-chloro-7-cyclohexyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (111 mg, 0.361 mmol) which gave tert-butyl 3-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (120 mg) in 55.1% yield. MS m/z 603.6 (M+H)+.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6]O.O.O.O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O>C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[C:26]#[N:6]
Reactant: NO
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(Cl)cccc1Cl
Yield: 61 %

Procedure:
A mixture of 3.7 g of hydroxylamine sulphate, 7 g of sodium acetate trihydrate, 17 g of acetic anhydride, 5 ml of acetic acid and 4.5 g of 2,6-dichlorobenzaldehyde was heated at reflux for 34 hours. Cooling, filtration and washing with water gave 2.7 g of pure 2,6-dichlorobenzonitrile. Stripping of the filtrate gave an additional 1 gram of pure 2,6-dichlorobenzontirile thus producing an overall yield of 84%.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[C:11]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[C:10]=1[OH:21]>C1(C)C=CC=CC=1>[N:5]([S:2]([O:21][C:10]1[C:9]([CH3:8])=[CH:20][CH:19]=[CH:18][C:11]=1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])(=[O:4])=[O:3])=[C:6]=[O:7]
Reactant: C=CCOC(=O)c1cccc(C)c1O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1cccc(C)c1OS(=O)(=O)N=C=O
Temperature: 110 °C

Procedure:
A solution of 3.7 g (0.026 mole) of chlorosulfonylisocyanate in 25 ml of absolute toluene are added dropwise to a solution of 4.8 g (0.025 mole) of allyl 3-methylsalicylate in 25 ml of absolute toluene, at 25° C. When the dropwise addition is complete, the temperature is increased slowly to 110° C., and the mixture is refluxed for 6 hours. The mixture is cooled and the solvent is removed on a rotary evaporator. The yellow oil remaining (7.5 g 100% of theory) is employed without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1nc2ccccc2o1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1nc2ccccc2o1
Yield: 44 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use benzo[d]oxazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 44% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.01 (t, J=5.5 Hz, 1H), 8.62 (d, J=8.1 Hz, 1H), 7.72-7.64 (m, 2H), 7.45-7.31 (m, 7H), 6.40 (dd, J=8.1, 2.7 Hz, 1H), 6.24 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.68 (d, J=5.5 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 473.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[CH3:22][C:3]1[C:2]([C:25]2[N:24]([CH3:23])[CH:28]=[CH:27][N:26]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1-c1nccn1C
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 2-(3-chloro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 425; 34.1 mg, 0.109 mmol), 1-methyl-2-(tributylstannyl)-1H-imidazole (Indofine Chemical Company, Inc.; 0.042 mL, 0.131 mmol) and Pd(PPh3)4 (Strem Chemicals, Inc.; 12.60 mg, 10.90 μmol) in toluene (2.0 mL) was stirred under argon at 110° C. for 1 h. The reaction mixture was then cooled to RT and diluted with hexanes (10 mL). The precipitated solid was collected by vacuum filtration (fine glass frit), sequentially washed with hexanes (10 mL) and Et2O (10 mL), and dried in vacuo to provide 2-(2-methyl-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (34.7 mg, 0.097 mmol, 89% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (1H, br. s.), 7.97 (1H, dd, J=7.1, 1.3 Hz), 7.91 (1H, s), 7.85 (1H, dd, J=8.2, 1.2 Hz), 7.75-7.82 (1H, m), 7.66 (1H, d, J=0.6 Hz), 7.07 (1H, d, J=2.0 Hz), 6.98 (1H, br. s.), 3.79 (3H, s), 3.42 (2H, td, J=6.8, 2.2 Hz), 2.88 (2H, br. s.), 2.83-2.86 (3H, m). m/z (ESI, +ve) 359.0 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:55])[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=5[F:35])[CH2:21]4)=[O:18])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH2:4][CH2:3]1>[Pd].C(OCC)(=O)C>[O:55]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:19][C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]5[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=5[F:35])[CH2:21]4)=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)c2ccc3c(c2)c(C2=CCS(=O)(=O)CC2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1CN1CCC[C@@H](NC(=O)c2ccc3[nH]nc(C4CCS(=O)(=O)CC4)c3c2)C1

Procedure:
A vial containing 3-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-N-[(3R)-1-(2-fluoro-6-methoxybenzyl)piperidin-3-yl]-1-trityl-1H-indazole-5-carboxamide (100 mg, 0.132 mmol) was charged with ethyl acetate (20 mL) to yield a homogenous solution. The resulting volume was continuously recycled through a 30 mm 10% Pd/C cartridge on a CatCart Thalesnano instrument (flow rate: 1 mL/min; temperature: 60° C.; pressure: 60 bar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3C(OC(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]3[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH3:30])[CH:39]([CH3:41])[CH3:40])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)indoline-1-carboxylate (1.41 g, 3.2 mmol) in DCM (20 mL) was added HCl (4M in dioxane, 4 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate was dissolved in DMF (30 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (560 mg, 3.2 mmol), HATU (1.22 g, 3.2 mmol), and DIPEA (2.79 mL, 16 mmol) were added sequentially. The solution stirred for 3 h, diluted with EtOAc, washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The mixture was purified by silica gel chromatography to yield product (600 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:16]([S:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(Br)nc1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(SCc2ccccc2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a solution of 2-bromo-5-methoxypyridine (1.13 g) in toluene (15 mL) were added phenylmethanethiol (820 mg), N,N-diisopropylethylamine (1.71 g), tris(dibenzylideneacetone)dipalladium(0) (220 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (278 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=49:1→19:1) to give the title compound as a yellow oil (yield 1.47 g, quantitative).