Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.C(Cl)Cl>[C:14]1([C:13]2[O:12][C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 210 °C
Yield: 85.6 %

Procedure:
A mixture of methyl 4-amino-3-hydroxy-benzoate 25a (0.3 g, 1.8 mmol) and benzoyl chloride 25b (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic solution was dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 25c (0.39 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([SH:13])[N:8]=2)=[CH:4][CH:3]=1.[CH3:14]I>O.[OH-].[Na+].CCO>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Sc1nccc(-c2ccc(Br)s2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nccc(-c2ccc(Br)s2)n1
Reaction time: 18 h
Yield: 88.3 %

Procedure:
4-(5-Bromothiophen-2-yl)-pyrimidine thiol (2.5 g, 9.15 mmol) was completely dissolved in 14.8 mL DI water and 2.4 mL 4 N NaOH. The mixture was diluted with EtOH (25 mL) and MeI (0.598 mL, 9.61 mmol) was added. The reaction was stirred 18 hours. The yellow solids were collected by filtration, washed with EtOH and dried to afford 4-(5-Bromothiophen-2-yl)-2-methylsulfanyl-pyrimidine (2.32 g, 88.6%) as a pale yellow solid. MS: m/z 287 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:20]1([CH2:26][C:27](=O)[C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].C([BH3-])#N.[Na+]>CO>[C:28]([CH:27]([NH:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:30])=[O:29]
Reactant: C[C@H](N)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(Cc1ccccc1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
L-Alanyl-N-(indan-2-yl)glycine (1.0 g) and 6.0 g of phenylpyruvic acid are dissolved in 50 ml of 70% aqueous methanol, and the pH is adjusted to 7.0 with aqueous potassium hydroxide. Sodium cyanoborohydride (1.0 g) is added to this solution. After allowing the mixture to stand at room temperature overnight, the solvent is distilled off under reduced pressure, the residue is dissolved in 2 ml of water, made adsorbed on a Dowex 50 (H+) [trade name of ion-exchange resin] column and eluted with 2% pyridine. The solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography using acetonitrile-methanol (4:1) as the developer to give 0.3 g of N-(1-carboxy-2-phenylethyl)-L-alanyl-N-(indan-2-yl)glycine as colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>O.C(N(CC)CC)C.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][NH:19][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([NH2:30])=[N:29][C:21]=2[NH2:20])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(C(=O)O)c(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NNC(=O)Cc2ccc(OCc3ccccc3)cc2)c(N)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of DMF (1 mL) of (4-benzyloxy-phenyl)-acetic acid hydrazide (46 mg) described in Manufacturing Example 8-1 were added triethylamine (0.10 mL), 2,6-diamino-nicotinic acid (30 mg) described in Manufacturing Example 10-2-4, HOBt (27 mg), and WSC (41 mg), which was stirred overnight at the same temperature. Water was added to the reaction solution, and the precipitated solids were filtered off to obtain the titled compound (47 mg) as a crude form. This compound was used directly as a crude form in the subsequent reaction.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([OH:26])=O)=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:69][C:70]1[S:74][N:73]=[C:72]([CH3:75])[N:71]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:69][C:70]3[S:74][N:73]=[C:72]([CH3:75])[N:71]=3)=[O:26])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Cc1nsc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
DIPEA (0.8 mL, 4.77 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (800 mg, 1.59 mmol), HATU (787 mg, 2.07 mmol) and 5-amino-3-methyl-1,2,4 thiadiazole (549 mg, 4.77 mmol) in DMF (110 mL). The resulting mixture was stirred at ambient temperature for 16 hours, water (150 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (950 mg).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)=[N:3]1.C([Li])CCC.CN(C)[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:21]=[O:22])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(C=O)cc2)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A stirred solution of 2.2 grams (0.009 mole) 4-(2-methyl-2H-tetrazol-5yl)phenyl bromide (prepared by the method of G. D. Diana et al., J. Med. Chem. 1993, 36, 3240-3250) in 70 mL of dry tetrahydrofuran was cooled to -70° C., and 7.4 mL (0.018 mole) of n-butyllithium (2.5M in hexanes) was added dropwise from a syringe. The resulting reaction caused the reaction mixture temperature to rise to about -50° C. The reaction mixture was again cooled to -70° C., and stirring was continued for about 30 minutes. After this time 0.8 mL (0.010 mole) of N,N-dimethylformamide was added during a 90 second period. The reaction mixture was then stirred for 30 minutes at ice-water bath temperature, after which time it was allowed to warm to ambient temperature. The reaction mixture was poured into 200 mL of an aqueous solution saturated with ammonium chloride. The mixture was stirred for about 90 minutes and then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with one 400 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 3:7 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.5 gram of 4-(2-methyl-2H-tetrazol-5-yl)benzaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][C:15](=[O:28])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(C)(C)C.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:9]2[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:12](=[O:13])[N:11]([CH2:14][C:15](=[O:28])[NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[N:10]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NCc2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
119 mg (0.23 mmol) of tert.-butyl[3-(4-chlorophenyl)-5-oxo-1-(2-oxo-2-{[3-(trifluoromethyl)-benzyl]amino}ethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-acetate from Example 420 are dissolved in 9 ml of dichloromethane and treated with 3 ml of trifluoroacetic acid. This is stirred for 24 hrs at RT. The reaction mixture is then treated with 10 ml of toluene and concentrated under reduced pressure. A further 10 ml of toluene are added, and the mixture again evaporated. This procedure is repeated once again. The crude product is then freed of solvent residues under high vacuum. 110 mg (quantitative) of the target compound are thus obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]2[NH:32][N:33]=[C:34]([C:35](O)=[O:36])[C:28]=2[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([F:18])([F:16])[F:17])=[C:7]([CH:9]2[CH2:10][CH2:11][N:12]([C:35]([C:34]3[C:28]4[CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30][C:29]=4[NH:32][N:33]=3)=[O:36])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Step A To a solution of 4-(5-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (11, 90 mg, 0.32 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (85 mg, 0.32 mmol), and diisopropylethylamine (0.17 mL, 0.96 mmol) in DMF (5.8 mL) was added EDCI (74 mg, 0.38 mmol) and HOBt (52 mg, 0.38 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (4×20 mL) and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% MeOH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl) piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (45) as a white film (120 mg, 80%): 1H NMR (300 MHz, DMSO-d6) δ 12.96 (br s, 1H), 7.76 (dd, J=9.0, 5.7 Hz, 1H), 7.61-7.51 (m, 1H), 7.30-7.18 (m, 1H), 5.34-5.16 (m, 1H), 4.76-4.58 (m, 1H), 4.53-4.38 (m, 2H), 3.65-3.52 (m, 2H), 3.22-3.01 (m, 2H), 2.60-2.43 (m, 3H, overlaps with solvent), 1.83-1.65 (m, 4H), 1.42 (s, 9H); ESI MS m/z 497 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].Cl.[NH:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:8][CH2:7]1>C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClCCl>[F:26][C:23]([F:24])([F:25])[C:20]1[CH:21]=[CH:22][C:17]([O:16][C:15]2[CH:14]=[C:13]([CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:9]2[CH2:8][CH2:7][N:6]([C:1]([Cl:4])=[O:2])[CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: O=C(Cl)Cl
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round-bottomed flask was fitted with a stirring bar and dropping funnel. To the reaction flask was added dichloromethane (30 mL) and the vessel was set to chill in an ice/water bath. To the flask was added 19% v/v phosgene in toluene (6 mL). 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (3.34 g, 9 mmol, from Example 1a, Step 5) was dissolved in a 15% v/v solution of diisopropylethylamine in dichloromethane and added to the chilled reaction flask slowly using the dropping funnel. Upon addition, the solution was stirred at 0° C. for 1 h. Upon completion of the reaction, the solvent and excess phosgene were removed in vacuo. A 0.2 M stock solution of the residue in dichloroethane was prepared for use in the next step (45 mL).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Reactant: BrCCCN1C=CC=CC1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.:145-147° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyridine hydrobromide as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>[OH:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1/[CH:14]=[CH:13]/[C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1c(O)cccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 517 %

Procedure:
To a thick-walled vessel was charged with 2-bromo-3-nitrophenol (1.16 g, 5.32 mmol), ethyl acrylate (666 mg, 0.72 mmol), tri-(o-tolyl)phosphine (65 mg, 0.21 mmol), palladium acetate (12 mg, 0.05 mmol), and triethylamine(10 mL). The vessel was then sealed and the resulting mixture was heated to 100° C. overnight. In the morning, the vessel was cooled to rt and the mixture was poured into water. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The residue was purified with silica gel flash chromatography by using hexane/ethyl acetate (2/1) as the eluant to give ethyl (2E)-3-(2-hydroxy-6-nitrophenyl)prop-2-enoate (883 mg, 70%): Rf0.16 (3/1 hexane/ethyl acetate); 1H NMR (CDCl3) δ 7.6(d, J=16.1 Hz, 1H), 7.05-7.23 (m, 3H), 6.71 (dd, J=16.1, 0.8 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([CH2:12][C:13](OC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.CCOCC>[OH:14][CH2:13][CH2:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH2:11]1
Reactant: COC(=O)CC1CC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(CCO)c2ccccc2N1
Yield: 55.4 %

Procedure:
A solution of 11 g (0.05 mol) of methyl (±)-2-oxo-1,2,3,4-tetrahydro-4-quinolineacetate in 50 ml of dioxane is poured dropwise while stirring under an inert atmosphere into a suspension of 2.65 g (0.07 mol) of lithium aluminium hydride in 250 ml of dry ether. The mixture is then heated for 4 h to reflux. After cooling, the reaction is hydrolysed by the slow addition of 10 ml of water with vigorous stirring. The suspension is filtered and the inorganic solid is washed with 20 ml of dioxane. The filtrate is evaporated and the oil obtained is ground in ether, causing it to crystallize. The solid is recrystallized in ethyl acetate. 5.3 g (55%) of (±)-4-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone, melting point 119°-120° C., are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@@H:18]([CH:20]4[CH2:22][CH2:21]4)[CH3:19])=[C:15]([C:23]([NH2:25])=[O:24])[CH:14]=[N:13][N:12]3[CH:26]=2)[CH:6]=[CH:7][CH:8]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:20]1([C@H:18]([NH:17][C:16]2[C:11]3[N:12]([CH:26]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[CH:4]=4)[CH:10]=3)[N:13]=[CH:14][C:15]=2[C:23]([NH2:25])=[O:24])[CH3:19])[CH2:22][CH2:21]1
Reactant: CC(C)C(=O)O
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1cccc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-4-(((1R)-1-cyclopropylethyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 87, 15 mg, 0.043 mmol), isobutyric acid (3.99 μl, 0.043 mmol) and triethylamine (8.97 μl, 0.064 mmol) in DMF (0.5 mL) was added BOP (18.99 mg, 0.043 mmol) followed by stirring at rt for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (8.7 mg, 48%). HPLC (condition H): retention time=1.69 minute. LC/MS (M+H)+=420.3. 1H NMR (500 MHz, MeOD) δ ppm 8.04 (1 H, s), 7.82 (1 H, d, J=1.9 Hz), 7.48-7.52 (2 H, m), 7.33 (1 H, t, J=7.9 Hz), 7.15 (1 H, d, J=7.5 Hz), 7.06 (1 H, d, J=1.7 Hz), 4.41 (2 H, s), 4.04 (1 H, qd, J=6.4, 6.2 Hz), 2.48 (1 H, spt, J=6.9 Hz), 1.44 (3 H, d, J=6.4 Hz), 1.16 (6 H, d, J=6.9 Hz), 1.09-1.15 (1 H, m), 0.50-0.63 (2 H, m), 0.32-0.40 (2 H, m).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)=[C:4]([CH3:25])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:35].[K+]>O>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([I:35])=[CH:3][C:4]=2[CH3:25])[N:10]=1)=[O:24]
Reactant: [I-]
Reactant: Cc1cc(N)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc(I)ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-{1-[(4-amino-2-methylphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 33)(400 mg, 1.17 mmol) in water (1.7 ml) in an ice-water bath (internal temperature 5° C.) was added concentrated sulphuric acid specific gravity 1.84 (165 μl, 3.10 mmol) and then a solution of sodium nitrite, super free flowing (90 mg, 1.305 mmol, Aldrich) in ice-cold water (0.5 ml) dropwise. The resulting yellow solution was stirred in an ice-water bath for 30 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (291 mg, 1.75 mmol, Acros) in ice cold ˜1 M sulphuric acid (3 ml). The mixture was allowed to warm to ambient temperature and then heated to 80° C. for 1 h. The mixture was allowed to cool to room temperature for 1 h and was then partitioned between ethyl acetate (50 ml) and water (50 ml). The phases were separated and the organic phase washed with water (20 ml), brine (20 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a dark red/brown oil (515 mg). The sample was loaded in dichloromethane and purified on silica 50 g using 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (223 mg); LCMS: (System 4) MH+=454, tRET=3.14 min.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:28]([CH2:33][CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: CCC(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g (3.61 mmol) of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) in DMF (14.43 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (0.361 g, 9.02 mmol). The grey slurry was stirred at 0° C. for 30 minutes. Then methyl 2-bromobutanoate (1.246 mL, 10.83 mmol) was added. The mixture was warmed to room temperature and stirred at room temperature for 1 h. The mixture was quenched with sat. NH4Cl. The mixture was extracted with ethyl acetate. The organic layer was washed with water, 1 M LiCl (2×), and sat. aq. NaCl solution. The organic layer was dried over Na2SO4 filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (80 g column; eluent: 10 to 35% EtOAc in hexanes) to give the title compound as the less polar, major diastereomer.
Reaction SMILES: CN1CCCC1=O.C[N:9]([C:36]1[CH:41]=CC=CC=1)[S:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:25]=[C:20]3[C:19](=[O:34])[C:18]=2[CH:35]=1)(=[O:12])=[O:11].[Cl-].[Cl-].[NH2:44][CH2:45][C:46]1[S:47]C=CN=1.C(N(CC)CC)C>CS(C)=O.O>[CH3:31][N:29]1[CH:30]=[C:26]([C:24]2[CH:25]=[C:20]3[C:19](=[O:34])[C:18]4[CH:35]=[C:14]([CH2:13][S:10]([NH:9][CH2:36][C:41]5[S:47][CH:46]=[CH:45][N:44]=5)(=[O:12])=[O:11])[CH:15]=[CH:16][C:17]=4[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=2)[CH:27]=[N:28]1
Reactant: NCc1nccs1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)NCc5nccs5)cc4c(=O)c3c2)cn1
Temperature: 180 °C
Reaction time: 1.5 h

Procedure:
N-Methyl-2-pyrrolidinone (13.3 ml) was added to N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide (627 mg, 1.33 mmol) and 2-aminomethylthiazole dichloride (1004 mg, 6.66 mmol) in a vial. Triethylamine (1.86 mL, 13.3 mmol) was added and the vial was sealed, the resulting solution was heated to 180° C. with stirring. After 1.5 h., the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.22 (d, 1H); 8.54 (d, 1H); 8.48 (s, 1H); 8.16 (m, 3H); 7.81 (d, 1H); 7.78 (dd, 1H); 7.71 (d, 1H); 7.63 (d, 1H); 7.41 (d, 1H); 7.33 (d, 1H); 4.67 (s, 2H); 4.43 (d, 2H); 3.88 (s, 3H). LRMS (APCI) calculated for C24H19N5O3S [M+H]+, 478.1; found 478.0.