Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=2)=[CH:15][CH:14]=1.Br[C:40]1[N:45]=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH:43]=[CH:42][CH:41]=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.O1CCCC1>[C:27]1([CH3:31])[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[N:22]=[C:21]([C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)[N:20]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:40]4[N:45]=[C:44]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=5)[CH:43]=[CH:42][CH:41]=4)=[CH:18][CH:17]=3)[N:24]=2)[CH:26]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: Cc1cccc(-c2nc(-c3ccc(Br)cc3)nc(-c3cccc(C)c3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(-c3ccc(-c4cccc(-c5ccccn5)n4)cc3)nc(-c3cccc(C)c3)n2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 60 ml of tetrahydrofuran cooled to −78° C. in which 1.25 g of 2-(4-bromophenyl)-4,6-di-m-tolyl-1,3,5-triazine obtained in Reference Example 2 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.85 g of 6-bromo-2,2′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 14 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (developing solvent hexane:chloroform=1:1 to 1:2) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 6-[4-(4,6-di-m-tolyl-1,3,5-triazin-2-yl)phenyl]-2,2′-bipyridyl (0.89 g, yield 61%). Its melting point is shown in Table 4. In this case, a distinct point of glass transition was not observed.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3O[CH2:18][CH2:19][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OCCN.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[N:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:18][CH2:19][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Reactant: NCc1ccccc1
Solvent: NCCO
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)N(Cc1ccccc1)CC2

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-I-(n-butyl)-5-phenyl-4H-pyrrolo[3,2-c] [l,8]naphthyridin-4-one when 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one is substituted for 3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one and n-butylamine is substituted for benzylamine. Furthermore, 1,2,3,5-tetrahydro-5-(3-chlorophenyl)-1-(2-hydroxyethyl)-2-methyl-4H-pyrrolo[3,2-c][1,8] naphthyridin-4-one may be produced by this procedure when 1-(3-chlorophenyl)-4-hydroxy-3-(2-hydroxypropyl)[1,8]naphthyridin-2-one is substituted for 3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one and 2-hydroxyethylamine is substituted for benzylamine.
Reaction SMILES: [S:1]([Cl:3])Cl.N1C=CC=CC=1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>ClCCl>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[S:1][Cl:3])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: ClSCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CCC)SCl
Reaction time: 0.25 h

Procedure:
22.7 g of sulphur dichloride in 100 ml of dichloromethane was cooled to -5° C. and a solution of 17.4 g of pyridine in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 15 minutes and a solution of 20.2 g of di(n-propyl)amine dissolved in 50 ml of dichloromethane was added, over 30 minutes, while the temperature was maintained between -5° and 0° C. The resulting solution was stirred for 2 hours, while the temperature was allowed to rise to ambient. The solution was filtered and the solvent was evaporated. 150 ml of diethyl ether was added, the resulting solution was filtered, and the filtrate evaporated. Distillation of the residue gave di(n-propyl)aminosulphenyl chloride (38B), b.p.: 94°-5° C. at 15 Torr.
Reaction SMILES: Cl.[CH2:2]([N:6]1[C@@H:10]([C:11](OC)=O)[CH2:9][S:8][C:7]1=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25])[CH:3]([CH3:5])[CH3:4].C(N1C(=C)C(=O)SC1=N[C:38]1[CH:43]=CC([N+]([O-])=O)=[CH:40][C:39]=1[CH3:47])C(C)C>CCOC(C)=O>[CH3:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:15]=[C:7]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[C:10]2([CH2:40][CH:39]3[CH2:47][CH:11]2[CH2:43][CH2:38]3)[CH2:9][S:8]1
Reactant: C=C1C(=O)SC(=Nc2ccc([N+](=O)[O-])cc2C)N1CC(C)C
Reactant: COC(=O)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CC3CCC2C3)N1CC(C)C

Procedure:
(R)-N-Isobutylserine methyl ester HCl salt (Method B3a; 2.28 g, 10.8 mmol) was treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a. The resulting material was purified by column chromatography (SiO2, gradient from hexane to 10% EtOAc/hex) to give 3-isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one (0.028 g, 10%) followed by (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt (0.192 g, 56%). 3-Isobutyl-4-methylene-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidin-5-one: TLC (25% EtOAc/hex) Rf 0.40. (S)-3-isobutyl-4-carbomethoxy-2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine HCl salt: TLC (free base, 25% EtOAc/hex) Rf0.50.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1.[ClH:18].[C:19](OCC)(=O)[CH3:20]>CN(C)C=O.O1CCOCC1.ICC>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[NH:17])[S:16][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2cccc(NC(N)=S)c2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCI
Solvent: C1COCCO1
Product: CCSC(=N)Nc1cccc(-c2cc(C)ccn2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3-(4-methylpyridin-2-yl)phenyl)thiourea (243 mg) in N,N-dimethylformamide (5 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml) and iodoethane (0.4 ml), and the mixture was stirred at 50° C. for 2 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration and dissolved in water. To the solution was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methylpyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (294 mg).
Reaction SMILES: CCN(C(C)C)[CH:4]([CH3:6])[CH3:5].[ClH:10].[NH2:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([Br:24])=[CH:22][N:21]=[C:20]3[NH:25][CH:26]=[C:27]([NH:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=4)[C:19]=23)[CH2:14]1.CC(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[ClH:10].[Br:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][C@@H:13]([CH2:12][NH:11][CH:4]([CH3:6])[CH3:5])[CH2:14]2)=[C:19]2[C:27]([NH:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=3)=[CH:26][NH:25][C:20]2=[N:21][CH:22]=1
Reactant: NC[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
DIEA (0.023 mL, 0.133 mmol) was added to a solution of (S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (70 mg, 0.13 mmol; Example 3A) and propan-2-one (77.4 mg, 1.33 mmol) in CH2Cl2:DMF (1:1, 3 mL), followed by the addition of NaBH(OAc)3 (57 mg, 0.26 mmol). The reaction was stirred for 30 minutes. The reaction mixture was then poured into a solution of Na2CO3 and extracted into CH2Cl2. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson system). The isolated product was then dissolved in minimal CH2Cl2 (with MeOH to aid solubility) and added to 1M HCl in ether (10 mL). The solid formed was collected to provide (S)—N-(5-bromo-4-(3-((isopropylamino)methyl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (40 mg, 53% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.08 (d, 1H), 10.58 (s, 1H), 9.32 (d, 1H), 8.98 (dd, 1H), 8.76 (dt, 1H), 8.32 (s, 1H), 7.99 (dd, 1H), 7.67 (d, 1H), 3.77-3.73 (m, 1H), 3.60-3.52 (m, 2H), 3.39-3.34 (m, 1H), 3.23-3.16 (m, 1H), 2.91-2.85 (m, 2H), 2.73-2.66 (m, 1H), 2.14-2.07 (m, 1H), 1.74-1.64 (m, 1H), 1.22 (d, 6H); LCMS (APCI+) m/z 459.1, 460.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][N:34]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)nc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccc(OC)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 90.5 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 2-methoxy-5-tributylstannanyl-pyridine (90 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-35% EtOAc/hexanes+1% AcOH) to give 67 mg of the title compound. MS: (+) m/z 494.39 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:4].[C:17]1(P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CI>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: c1ccc2c(P(c3cccc4ccccc34)c3cccc4ccccc34)cccc2c1
Reactant: COC(=O)c1cc(B(O)O)cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1cc(C)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 683.2 %

Procedure:
Following a general procedure from Applied Organometallic Chemistry 2004, 18, 602-604, a solution of 3-(methoxycarbonyl)-5-nitrophenylboronic acid (900 mg, 4.0 mmol) in tetrahydrofuran (16 mL) was added to a round bottom flask charged with palladium acetate (27 mg, 0.12 mmol), tri-1-napthylphosphine (112 mg, 0.27 mmol), potassium phosphate (1.70 g, 8.00 mmol), and methyl iodide (0.370 mL, 5.9 mmol) under nitrogen atmosphere. Water (0.14 mL, 7.8 mmol) was added and the mixture was stirred overnight at rt. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient from 0 to 40% ethyl acetate in hexanes) to give 89A (0.36 g, 46%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.54 (s, 3H) 3.98 (s, 3H) 8.19 (s, 1H) 8.23 (s, 1H) 8.67 (s, 1H).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]1[CH2:32][C:30](=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.O>C1COCC1>[CH2:2]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:32]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCc2ccccc21
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: C=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
N-Butyl lithium (Aldrich) (47 cm3, 74.8 mmol, 1.6 M solution in hexane) was added dropwise to a solution of methyl triphenylphosphonium iodide (Aldrich) (27.65 g, 68 mmol) in dry THF (150 cm3), under nitrogen at 0° C. α-Tetralone (Aldrich) (10 g, 68 mmol) in dry THF (100 cm3 was then added dropwise and the mixture stirred for 17 hours at room temperature. The reaction mixture was then added to water and extracted with ethyl acetate. The combined extracts were then dried (Na2SO4), filtered and concentrated in vacuo. Purification was by column chromatography on a neutralised silica column (Et3N) (Eluant: Pet. Ether 40-60° C.) produced a colourless mobile oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:14]([Cl:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccc(O)c(Cl)c1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1Cl
Temperature: 60 °C

Procedure:
3-(3-Chloro-4-hydroxy-phenyl)-propionic acid benzyl ester (step 1) (5.9 g, 20.3 mmol) in DMF (60 ml) was treated with potassium carbonate (5.61 g, 40.6 mmol) followed by t-butyl bromoacetate (4.49 ml, 30.4 mmol) and the mixture was heated at 60° C. overnight. The reaction mixture was diluted with water (500 ml), and the product extracted into EtOAc (450 ml). The organic portion was washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield a yellow oil. Purification by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the title product; 1H NMR (400 MHz, DMSO-d6) δ 7.34 (6H, m), 7.11 (1H, d), 6.89 (1H, d), 5.07 (2H, s), 4.74 (2H, s), 2.81 (2H, t), 2.68 (2H, t), 1.42 (9H, s). LC-MS Rt 1.64 mins; 427.3 [M+Na]+, Method 2minLC_v002.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][NH2:15]>C1COCC1>[Br:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:11][N:15]([CH3:14])[C:3]2=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)ccc1CBr
Reactant: CN
Solvent: C1CCOC1
Product: CN1Cc2ccc(Br)cc2C1=O
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50° C. for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH:27]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C@H:31]2[CH3:36])[CH2:29][CH2:28]1>>[CH:27]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:21])[CH2:32][C@H:31]2[CH3:36])[CH2:29][CH2:28]1
Reactant: C[C@@H]1CNCCN1C1CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C4CC4)[C@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-cyclopropyl-2-methylpiperazine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26 (br. s., 1H) 0.36-0.51 (m, 2H) 0.61 (d, J=5.56 Hz, 1H) 0.93-1.29 (m, 3H) 1.65 (br. s., 1H) 2.16-2.40 (m, 1H) 2.43 (s, 3H) 2.58 (br. s., 1H) 2.75-3.03 (m, 2H) 3.15 (br. s., 1H) 3.43-3.59 (m, 1H) 4.09 (br. s., 1H) 7.66 (d, J=8.32 Hz, 1H) 7.73 (s, 1H) 7.78 (d, J=8.08 Hz, 1H) 8.06 (dd, J=8.59, 2.02 Hz, 1H) 8.15 (s, 1H) 8.38 (br. s., 1H) 8.53 (d, J=1.77 Hz, 1H); ESI-MS m/z [M+H]+ 443.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[S:6])[NH2:5].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[S:6][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:5]=1
Reactant: COCC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(COC)n1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A solution containing the product from Example 6B (7 g, 66.6 mmol) in acetone (270 mL) was treated with ethyl bromopyruvate (8.4 mL, 66.6 mmol) and magnesium sulfate (7.9 g, 66.6 mmol), heated at reflux for 16 hours, cooled to 25° C., filtered and concentrated. The residue was chromatographed on silica gel eluting with chloroform to give the title compound (7.6 g, 57% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[C:20]=1[CH3:21].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]1[N:17]=[CH:18][N:19]([C:22]2[CH:23]=[C:24]([NH:25][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:26]=[CH:27][CH:28]=2)[C:20]=1[CH3:21]
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Reactant: Cc1ncn(-c2cccc(N)c2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncn(-c2cccc(NC(=O)c3cccc4c(C)c(C)[nH]c34)c2)c1C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
To a suspension of 2,3-dimethyl-1H-indole-7-carboxylic acid (95 mg) and 3-(4,5-dimethylimidazol-1-yl)aniline (94 mg) in dichloromethane (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) and 4-dimethylaminopyridine (31 mg), and the mixture was stirred for 12 hours. The mixture was diluted with dichloromethane and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with dichloromethane, and the insoluble material was collected by filtration and dried to give N-[3-(4,5-dimethyl-imidazol-1-yl)-phenyl]-2,3-dimethyl-1H-indole-7-carboxamide (77 mg, 43.0%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[S:22]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 91.8 %

Procedure:
To a stirred solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g, 23.2 mmol) in anhydrous pyridine (18.5 mL) at 0° C. under nitrogen, p-toluenesulfonyl chloride (4.87 g, 25.55 mmol) was added in one portion. The reaction was stirred at 0° C. for 100 minutes before warming to RT. After 18 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with aqueous hydrochloric acid (2×100 mL, 1.0 M solution), saturated sodium chloride solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield the title compound (7.87 g, 91%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH:23]C(=O)C(F)(F)F)=[CH:18][C:17]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([NH2:23])=[CH:18][C:17]=3[O:30][CH3:31])[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C(F)(F)F)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
A mixture of N-(1-cyclohexylmethylpiperid-4-yl)-2-methoxy-4-trifluoroacetamido-5-chlorobenzamide (8.1 g; 0.017 moles), ethanol (25 ml), water (15 ml) and 8 N sodium hydroxide aqueous solution (25 ml) was stirred for 12 hours at room temperature. After dilution with water, the mixture was extracted with chloroform and the chloroformic solution dried (Na2SO4) and evaporated in vacuo. N-(1-Cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (5 g) was obtained. It was converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 225°-227° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])OC(=O)[N:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[C:16]([C:20]1[CH:37]=[CH:36][C:23]([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[C:16]([C:20]1[CH:37]=[CH:36][C:23]([CH2:24][N:25]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C:10](=[O:12])[C:11]2[C:6]([NH:7][CH3:14])=[CH:5][CH:4]=[C:3]([F:15])[C:2]=2[Cl:1])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Cn1c(=O)oc(=O)c2c(Cl)c(F)ccc21
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1ccc(F)c(Cl)c1C(=O)N(CCc1ccc(Cl)c(Cl)c1)Cc1ccc(C(C)(C)C)cc1
Temperature: 140 °C
Yield: 27.1 %

Procedure:
A mixture of 5-chloro-6-fluoro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (83 mg, 0.36 mmol) and (4-tert-butylbenzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (122 mg, 0.36 mmol) in DMF (2 ml) was heated to 140° C. for 2 h and then at 110° C. overnight. The reaction mixture was then cooled to RT and the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography to give the desired product (51 mg, 27%) as a white solid. MS (ISP) 521.9 (M+H)+.