Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(Cl)Cl.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C([O-])(O)=O.[Na+]>O>[Cl:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([Cl:23])[C:17]([F:24])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 2 h

Procedure:
38 g of ethoxy acrylate from Example 1 are initially introduced into 150 ml of methylene chloride. An aqueous solution of 15.4 g of ethyl 3-aminopropionate hydrochloride is added to this. A solution of 8.4 g of NaHCO3 in water is added dropwise to the two-phase system with vigorous stirring. After completion of the dropwise addition, the mixture is stirred for a further 2 hours, and the phases are subsequently separated.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.[CH:18]([N:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>>[NH2:9][C:3]1[N:4]=[C:5]([NH:8][C:26]([C:25]2[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23][CH:24]=2)=[O:27])[CH:6]=[CH:7][C:2]=1[I:1]
Reactant: CC(C)n1nccc1C(=O)O
Reactant: Nc1ccc(I)c(N)n1
Solvent: Cc1cccc(C)n1
Product: CC(C)n1nccc1C(=O)Nc1ccc(I)c(N)n1
Yield: 38 %

Procedure:
Method A using 3-Iodo-pyridine-2,6-diamine (Preparation 44), 1.6 equivalents of lutidine and 1.5 equivalents of acid chloride prepared from 2-isopropyl-2H-pyrazole-3-carboxylic acid. Purified by trituration with methanol:ethylacetate 1:2 to afford the title compound as a colourless oil (608 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[F:1][C:2]1[CH:10]=[C:6]([C:7]([NH:20][C@H:21]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:9])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(F)cnc1Cc1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(F)cnc2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorobenzyl)nicotinic acid (step 3 of Example 58) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 9.13 (1H, d, J=7.7 Hz), 8.59 (1H, d, J=3.0 Hz), 7.93 (2H, d, J=8.4 Hz), 7.79 (1H, dd, J=8.7, 2.8 Hz), 7.51 (2H, d, J=8.2 Hz), 7.15–7.09 (2H, m), 7.03–6.96 (2H, m), 5.19–5.09 (1H, m), 4.17 (1H, d, J=13.7 Hz), 4.08 (1H, d, J=13.7 Hz), 3.85 (3H, s), 1.42 (3H, d, J=7.1 Hz); MS (ESI) m/z 411 (M+H)+, 409 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=4)[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@H]23)nc1
Reactant: Fc1cccc(C(F)(F)F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(N2CCN3CC[C@@H](Oc4ccc(Cl)cn4)[C@H]3C2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of Example 101B (53 mg, 0.21 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (41 mg, 0.25 mmol) in dimethyl sulfoxide (0.7 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.73 mmol). The mixture was heated to 90° C. and stirred for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=248 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.81-1.96 (m, 1 H), 2.13-2.31 (m, 3 H), 2.40-2.53 (m, 1 H), 2.94-3.05 (m, 2 H), 3.16-3.25 (m, 2 H), 4.34-4.43 (m, 1 H), 4.50 (dd, 1H, J=12, 3 Hz), 5.59 (ddd, 1H, J=7, 4, 2 Hz), 6.81 (d, 1H, J=8 Hz), 6.96 (dd, 2H, J=8, 5 Hz), 7.61-7.71 (m, 2 H), 8.12 (d, 1H, J=2 Hz); MS (DCI) m/z 399 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)#[CH:25].C(NCC)C>CN(C=O)C.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>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]#[C:25][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][C:6]4[CH2:23][C:13]5([C:21]6[C:16](=[N:17][CH:18]=[CH:19][CH:20]=6)[NH:15][C:14]5=[O:22])[CH2:12][C:7]=4[CH:8]=3)[N:3]=2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc(C#Cc2ccc3cc4c(cc3n2)CC2(C4)C(=O)Nc3ncccc32)cc1
Temperature: 120 °C

Procedure:
A stirred mixture of (±)-2-chloro-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (15 mg, 0.047 mmol, described in Intermediate 20), 4-ethynyltoluene (7 mg, 0.061 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol), and diethylamine (0.073 mL, 0.70 mmol) in DMF (0.5 mL) was heated at 120° C. in a microwave reactor for 5 min. The cooled mixture was partitioned between saturated aqueous NaHCO3 (3 mL) and EtOAc (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined and concentrated to give a crude product. This was further purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to give the title compound. MS: m/z=402 (M+1). HRMS: m/z=402.1609; calculated m/z=402.1601 for C27H20N3O.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1>O1CCCC1>[OH:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:23])=[CH:16][CH:17]=1)[C:2]#[C:1][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC1(O)CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a solution of 1-ethynylcyclohexanol (500 mg, 4.02 mmol) in tetrahydrofuran (20 mL), 2.77 M n-butyllithium (solution in n-hexane, 3.6 mL, 9.90 mmol) was added dropwise at −78° C., and the obtained solution was stirred at the same temperature for 1 hour. To the reaction solution, p-tolualdehyde (0.52 mL, 4.40 mmol) was added at −78° C., and the obtained solution was allowed to warm gradually to room temperature with stirring. To the reaction solution, distilled water and 1 M hydrochloric acid were added to make the mixture acidic, and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (598 mg, 2.44 mmol, 61%) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C[O:7][C:8](=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1>CO.O>[OH:3][NH:2][C:8](=[O:7])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:27])[CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1
Reactant: COC(=O)C=Cc1cccc(NC(=O)C=Cc2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1cccc(NC(=O)C=Cc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.14 g, 2.01 mmol) (Acros) in methanol (2.0 ml) a solution of NaOH (0.16 g, 4.00 mmol) in H2O (0.2 ml) was added and the resultant mixture was stirred at ambient temperature for 5 min. To the reaction mixture a 3-[3-(3-phenylacryloylamino)-phenyl)-acrylic acid methyl ester (8) (0.15 g, 0.49 mmol) solution in methanol (2.0 ml) was added and stirred at ambient temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was crystallized from ethyl acetate-methanol giving pure title compound (0.040 g, 26%), m.p. 178° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.45 (d, 1H, J=16.0 Hz); 6.85 (d, 1H, J=16.0 Hz); 7.14-7.76 (m, 10H); 8.00 (br s, 1H); 9.03 (br s, 1H); 10.32 (br s, 1H); 10.83 (br s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 4.5% (column size 4.6×150 mm; mobile phase acetonitrile −0.1% H3PO4, gradient from 30 to 100%; sample concentration 0.25 mg/ml; flow rate 1.5 ml/min; detector: UV 270 nm). Anal. Calcd for C18H16N2O3×0.25 H2O, %: C, 69.11, H, 5.32, N, 8.95. Found, %: C, 69.09, H, 5.06, N, 8.81.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[CH2:7][CH2:6]1)C.C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C=O)C>[NH2:27][C:26]1[N:28]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=3[C:13]=2[N:25]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
To a solution of 16.62 g (60 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-methyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 0.5 L of DMF, 27 g (150 mmol) of guanidine carbonate was added. The mixture was stirred at 110° C. overnight. After cooling the mixture was poured into water (2.5 L) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 26.83 g of title compound (91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11a, and 1-methyl-1 H-imidazole-4-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.99 (d, 1H), 8.63 (m, 1H), 8.50 (d, 1H), 7.88 (d, 2H), 7.55 (s, 1H), 7.42 (s, 1H), 7.32 (d, 2H), 7.13 (m, 1H), 7.04-6.97 (m, 3H), 4.47 (s, 2H), 4.41 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 506 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].[C:23](N1C=CN=C1)(N1C=CN=C1)=[S:24]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[C:12]4[N:11]([C:23](=[S:24])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC1=C(c2ccc(Cl)cc2)n2ncc(C(N)=O)c2NC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(c2ccc(Cl)cc2)n2ncc3c(=O)[nH]c(=S)n(c32)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 5.0 g of 7-(4-chlorophenyl)-4,5-dihydro-6-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 35) and 0.2 liters of dry tetrahydrofuran is stirred and cooled to -78° C. in a dry ice-acetone bath, then 1.43 g of sodium hydride (60 percent dispersion in mineral oil) is added in one portion. This mixture is stirred for 0.5 hours, then 3.19 g of 1,1 '-thiocarbonyldiimidazole is added and stirring is continued at -78° C. for 2 hours. The mixture is allowed to warm to room temperature and is stirred for 48 hours and then the reaction is quenched with 0.5 liters of water and neutralized with 5 percent aqueous hydrochloric acid. The crystalline solid that forms is collected, washed with ether and dried to give 4.2 g of the desired product as cream colored crystals, mp. 283-285° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)Cl>[Br:17][C:7]1[N:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cnc(CC)c(NC(CC)CC)n1
Solvent: ClCCl
Product: CCc1nc(NC(CC)CC)c(CC)nc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A 500 mL dry round bottom flask equipped with a magnetic stir bar was charged with 3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (10.0 g, 45.18 mmol) and CH2Cl2 (220 mL). After the mixture was cooled with an ice bath, N-bromosuccinimide (8.84 g, 49.7 mmol) was added at once. The mixture was stirred at 0° C. for 30 minutes then quenched with saturated aq. NaHCO3, diluted with H2O and extrated twice with CH2Cl2. The organics were combined, dried with NaSO4, filtered and concentrated to 13.96 g of a brown oil. The crude was purified by Biotage MPLC in two batches (120 g columns, 2.5% ethyl acetate in heptane.) Like fractions were combined to give 11.57 g (85%) of 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B(O)O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C(O)C>[CH:14]1[C:22]2[C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19][C:18]=2[C:17]([C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:2]4[CH:7]=[C:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=[CH:4][N:3]=4)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:16][CH:15]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: OB(O)c1cccc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(-c3cccc(-c4cccc(-c5cccc6c5sc5ccccc56)c4)c3)ncn2)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Then, 1.0 g of 4-chloro-6-phenylpyrimidine obtained in Step 1, 2.0 g of 3′-(dibenzothiophen-4-yl)-3-biphenylboronic acid, 5.3 mL of a 2M aqueous solution of potassium carbonate, 24 mL of toluene, and 3.0 mL of ethanol were put into a 100-mL three-neck flask equipped with a reflux pipe. Degasification by stirring under a reduced pressure was performed and the air in the flask was replaced with nitrogen. To this mixture, 61 mg of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added and the mixture was heated at 80° C. for 7 hours to cause a reaction. An organic layer was extracted from the obtained mixture with the use of toluene and was washed with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate was added and gravity filtration was performed. After the solvent in this solution was distilled off, the obtained residue was dissolved in hot toluene and subjected to hot filtration through a filter aid in which Celite, alumina, Celite, Florisil, and Celite were stacked in this order. The solvent was distilled off and the obtained solid was recrystallized with toluene, so that 1.9 g of a white solid was obtained in a yield of 71%. Synthesis Scheme (D-2) of Step 2 is shown below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([CH3:15])[CH2:13][C:12]3[C:8]4[C:9](=[N:32][CH:33]=[CH:34][C:7]=4[C:6]=2[CH:35]=1)[NH:10][C:11]=3[C:16]1[CH2:17][CH:18]2[N:24](C(OC(C)(C)C)=O)[CH:22]([CH:23]=1)[CH2:21][CH2:20][CH2:19]2.FC(F)(F)C(O)=O>ClCCl>[CH:18]12[NH:24][CH:22]([CH2:21][CH2:20][CH2:19]1)[CH:23]=[C:16]([C:11]1[NH:10][C:9]3[C:8]4[C:12]=1[CH2:13][N:14]([CH3:15])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:35][C:6]=1[C:7]=4[CH:34]=[CH:33][N:32]=3)[CH2:17]2
Reactant: CN1Cc2c(C3=CC4CCCC(C3)N4C(=O)OC(C)(C)C)[nH]c3nccc(c23)-c2cc(F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1Cc2c(C3=CC4CCCC(C3)N4)[nH]c3nccc(c23)-c2cc(F)ccc21

Procedure:
A solution of Example 99C (1.135 g, 2.392 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) at room temperature for 30 minutes, and concentrated in vacuo. The crude product (LC-MS 375.2 (M+H)+) was directly used for next step.
Reaction SMILES: C([C:3]1[N:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)=[CH:7][C:4]=1[C:5]#[N:6])C.Cl.[NH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:37][NH:36][C:5](=[NH:6])[C:4]1[CH:7]=[C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)[CH:9]=[N:10][CH:3]=1
Reactant: CCc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 80 °C
Yield: 186.2 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinonitrile (described in Example 6, 0.10 g, 0.24 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (0.033 g, 0.48 mmol) and potassium carbonate (0.076 g, 0.72 mmol). The reaction mixture was heated to reflux at 80° C. for 16 h. The ethanol solvent was evaporated under reduced pressure and the residue was dissolved in DCM, and washed with water. The organic layer was dried, filtered and concentrated to provide N-hydroxy-5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinimidamide (0.2 g) which was used without further purification. LCMS Method X: retention time 1.788 min; [M+1]=448.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][O:11][CH3:15])[CH2:7][C:6]=2[CH:12]=1
Reactant: OCC1Cc2cc(F)ccc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1Cc2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
To a solution of (5-fluoro-2,3-dihydrobenzofuran-2-yl)methanol (854) (1.0 g, 6.0 mmol) in dimethylformamide (130.0 mL) was added 60% NaH in mineral oil (0.480 g, 12.0 mmol) and MeI (1.12 mL, 18.0 mmol). The suspension was stirred at room temperature for 24 h and diluted with water (50 mL), and extracted with ethyl acetate (2×25 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (0-10% EtOAc in hexanes) to provide the desired 5-fluoro-2-(methoxymethyl)-2,3-dihydrobenzofuran (855) (0.650 g, 59.5%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 90.4 %

Procedure:
A mixture of 5.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 g of methyl 6-bromohexanoate and 5.4 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethylformamide was stirred and heated at 75° for 10 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on 125 g of silica gel. Elution with 25% ethyl acetate-hexane gave 7.5 g (90% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][CH:30]=2)[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1-c1ccnc2ccccc12
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(-c2ccnc3ccccc23)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(5-methyl-2-quinolin-4-yl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as red solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:20][CH2:19]3)[N:13]=2)[CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].N#N>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:20][CH2:19]2)[N:13]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C3CC3)n2)c(C(N)=O)nn1
Temperature: 150 °C

Procedure:
To a stirred solution of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (104 mg, 359 mmol) in N-methyl-2-pyrrolidinone (5 mL) was added DMAP (47 mg, 377 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (154 mg, 718 μmol). The mixture was heated to 150° C. for 1.5 days, then a stream of N2 was blown into the flask while heating at 140° C. to evaporate the volatile solvents. The residue obtained was then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to afford tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3 ylamino)cyclohexylcarbamate (126 mg, containing some residual NMP) as a brown viscous oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.45 (s., 9H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 468 [M+H]. This was used directly in the next step without further purification.