Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:23]([C:27]#[CH:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:21]=[C:20]([C:28]#[C:27][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: O=C(NCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Yield: 72 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (72%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.45 (br s, 1H), 10.45 (s, 1H), 8.50 (t, J=5.4 Hz, 1H), 7.96 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.65 (s, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.49 (q, J=5.9 Hz, 2H), 3.29-3.24 (m, 2H), 0.24 (s, 9H). HRMS (FAB+) calcd C19H23FN3O3Si (MH+) 388.1493, found 388.1488.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[BrH:10].O>C1C=CC=CC=1>[Br:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCCCCCO
Reactant: Br
Solvent: O
Solvent: c1ccccc1
Product: OCCCCCCCBr
Reaction time: 12 h
Yield: 62 %

Procedure:
Heptane-1,7-diol (36.0 g, 272 mmol; Alfa Aesar) and aq. 48% HBr (38 mL) were heated under reflux in benzene (400 mL) with water removal using a Dean-Stark apparatus. After 12 h, all volatiles were removed in vacuo and the residue was purified by SiO2 column chromatography using a gradient of 10-30% EtOAc/hexanes as eluent to give 7-bromoheptan-1-ol (26.22 g, 62%) as colorless oil. TLC: 50% EtOAc/hexanes, Rf≈0.4; 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H, J=7.1 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.80-1.88 (m, 2H), 1.52-1.58 (m, 2H), 1.30-1.46 (m, 6H).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][C:5]=1[C:11]([O:13]C)=[O:12]>C1COCC1.CO>[Cl:3][C:4]1[C:8]([CH:9]=[O:10])=[CH:7][NH:6][C:5]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1[nH]cc(C=O)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1c[nH]c(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
LiOH (1 N in water, 2 mL, 2 mmol) was added to a solution of methyl 3-chloro-4-formyl-1H-pyrrole-2-carboxylate (0.050 g, 0.26 mmol) in THF (2 mL) and methanol (2 mL). The solution was stirred at RT overnight. The solvents were evaporated to afford a residue which was partitioned between EtOAc and 1 N HCl. The organic layer was separated, dried over MgSO4, filtered and evaporated to a solid to afford the title compound (0.038 g, 83%) as a crude product which was used with no further purification. 1H NMR (400 MHz, Acetone-d6) δ ppm 11.76 (br. s., 1H), 9.90 (s, 1H), 7.72 (d, 1H). LCMS: m/z=174.2 (M+1).
Reaction SMILES: N1N(C2C=CC(C(F)(F)F)=CC=2C(O)=O)N=CC=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.[N:37]1[NH:38][N:39]=[CH:40][CH:41]=1.Br[C:43]1[C:51]([F:52])=[CH:50][C:49]([F:53])=[CH:48][C:44]=1[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[F:52][C:51]1[C:43]([N:38]2[N:39]=[CH:40][CH:41]=[N:37]2)=[C:44]([CH:48]=[C:49]([F:53])[CH:50]=1)[C:45]([OH:47])=[O:46]
Reactant: O=C(O)c1cc(F)cc(F)c1Br
Reactant: c1cn[nH]n1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(F)cc(F)c1-n1nccn1

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 1.0 g, 10.86 mmol) and 2-bromo-3,5-difluorobenzoic acid (CAS number 651027-01-9; 1.27 g, 5.43 mmol) in 1,4-dioxane (5 ml) and water (1 ml). The crude solid was purified by using column chromatography (silica, 0-3% methanol/DCM) to afford 3,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 40a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 3,5-difluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 40b).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.[SH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>C(O)C.[OH-].[Na+]>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[N:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: SCc1ccccn1
Reactant: Clc1nc2cc3ccccc3cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(CSc2nc3cc4ccccc4cc3[nH]2)nc1
Yield: 51.4 %

Procedure:
0.92 g of 2-chloro-1H-naphth[2,3-d]imidazole and 0.57 g of 2-mercaptomethylpyridine were heated under reflux for 18 hours in 15 ml of ethanol and 4.5 ml of 1 N caustic soda. 50 ml of water were added to the reaction solution, which was then extracted twice with a total amount of 50 ml of ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and evaporated to dryness on a rotary evaporator. Crystallisation from 50 ml of acetonitrile provided 0.68 g of 2-[(2-pyridylmethyl)thio]-1H-naphth[2,3-d]imidazole having a m.p. of 169°-170°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)=[O:4].[C:15]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:17])[CH3:16].N1CCCCC1>N1C=CC=CC=1>[OH:28][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:15](=[O:17])[CH:16]=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:8]=1
Reactant: COC(=O)COc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a mixture of 1.43 g of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.50 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone and 6 ml pyridine was added 0.1 ml of piperidine, and this was heated under reflux for 1 hour. After cooled to room temperature, precipitated crystals were filtered, and washed with tetrahydrofuran to obtain 0.63 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (7e)] as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[Cl:18])[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: NCc1ccccc1Cl
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ccccc2Cl)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-chlorobenzylamine and DBU in DME. EI-MS m/e (%): 327 (M{37Cl}+, 10), 325 (M{35Cl}+, 35), 290 ([M—Cl]+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[CH:19]=[C:18]([Cl:28])[N:17]=1>O1CCOCC1>[Cl:28][C:18]1[N:17]=[C:16]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[C:25]2[C:24](=[O:26])[N:23]([CH3:27])[CH:22]=[N:21][C:20]=2[CH:19]=1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Reactant: Nc1nc(CO)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cnc2cc(Cl)nc(Nc3nc(CO)cs3)c2c1=O
Temperature: 80 °C

Procedure:
(2-aminothiazol-4-yl)methanol (70.0 mg, 0.54 mmol) and K2CO3 (148.6 mg, 1.08 mmol) were added to a solution of 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (123.7 mg, 0.54 mmol) in 1,4-dioxane (2.7 mL). The reaction mixture was heated at 80° C. overnight, cooled down, quenched with H2O (20 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (10% methanol/dichloromethane) to give 7-chloro-5-(4-(hydroxymethyl)thiazol-2-ylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O.N>C(Cl)(Cl)Cl>[Cl:18][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:15]
Reactant: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CCl
Temperature: 0 °C

Procedure:
1.00 g (4.47 mmol) of the compound from Example 31A are initially charged in 15 ml of chloroform, and 1.5 ml (16.10 mmol) of phosphoryl chloride are added carefully. With stirring, the reaction mixture is heated at reflux for 30 min. The mixture is then cooled to 0° C. and made weakly basic by addition of ammonia. The mixture is extracted three times with in each case 20 ml of ethyl acetate. The combined organic phases are washed twice with in each case 5 ml of water and then dried over magnesium sulfate. The solvent is removed on a rotary evaporator. The residue is used without further purification in the subsequent steps.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28](I)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.CCN(CC)CC>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.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:37]5[CH:36]=[N:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cnc3sc(-c4ccc(OC5CCN(C(=O)OC(C)(C)C)CC5)c(OC)c4)nn23)cn1
Temperature: 120 °C
Yield: 13.2 %

Procedure:
A mixture of 4-[4-(5-iodo-imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-methoxy-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (94 mg, 0.169 mmol, 1 eq), 2-methoxy-5-pyridineboronic acid (39 mg, 0.253 mmol, 1.5 eq), EtOH (5 ml), Et3N (0.070 ml, 0.507 mmol, 3 eq) and Pd(PPh3)2Cl2 (12 mg, 0.0169 mmol, 0.1 eq) was heated under microwave irradiation (120° C., 30 min). The solvents were removed under reduced pressure and the residue was treated with Et2O. The filtrate was evaporated and the residue was purified by HPLC to give the desired product (12 mg; 13%) as a colourless oil. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.30 min, [M+H]+ m/z 538.3; 1H NMR (300 MHz, CD3COCD3) δ 8.87 (m, 1H), 8.28 (dd, J=8.7, 2.5 Hz, 1H), 7.64 (s, 1H), 7.59 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.7, 0.7 Hz, 1H), 4.71 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.75 (m, 2H), 3.32 (m, 2H), 1.98 (m, 2H), 1.70 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=O.[Br-].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7](/[CH:8]=[CH:34]/[C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][N:26]=2)[CH:10]=1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.6 %

Procedure:
A solution of 5-methoxy-4-[3-(morpholin-4-yl) propyloxy]-2-nitrobenzaldehyde (0.26 g, 0.79 mmol) obtained in Step 1 in methanol (8.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.73 g, 1.5 mmol) and potassium carbonate (0.34 g, 2.8 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and the precipitated solid was triturated in methanol to obtain (E)-3-{2-[5-methoxy-4-[3-(morpholin-4-yl)propyloxy]-2-nitrophenyl]vinyl}-1H-indazole (0.39 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3.CCN(CC)CC.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>O1CCOCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3
Reactant: Cc1cc2nc(Cl)c3ccc(Br)cc3c2c(Cl)n1
Reactant: NCc1ccccn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc2nc(NCc3ccccn3)c3ccc(Br)cc3c2c(Cl)n1
Temperature: 120 °C

Procedure:
To a solution of 9-bromo-1,6-dichloro-3-methyl-benzo[c][1,6]naphthyridine (0.12 g, 0.35 mMol) in anhydrous dioxane (4 mL) was added anhydrous Et3N (0.07 mL, 0.53 mMol), followed by 2-aminomethylpyridine (0.038 g, 0.35 mMol). The resulting reaction mixture was heated in a sealed tube at 120° C. for 5 hours. The reaction mixture was concentrated to a crude solid that was redissolved in EtOAc (10 mL). The EtOAc layer was washed with water (2×5 mL), brine (1×10 mL) and dried over MgSO4. The filtrate was concentrated and the resulting residue was purified by flash chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-1-chloro-3-methyl-N-(pyridin-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) 9.88 (d, 1H), 8.65 (bs, 1H), 7.97 (d, 1H), 7.83-7.80 (dd, 1H), 7.75 (t, 1H), 7.64 (bs, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 4.99 (d, 2H), 2.62 (s, 3H). LRMS calculated for C19H14BrClN4 [M+H]+, 415.0; found 415.1.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]([NH:13][NH2:14])=[O:12].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:44])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:42])[F:41])=[N:30][N:29]=2)[CH3:27])=[C:20]([CH:24]=1)[C:21]([OH:23])=O.O>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][C:26]([CH3:27])([C:28]2[N:32]([CH3:33])[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:41])([F:43])[F:42])=[N:30][N:29]=2)[CH3:44])=[C:20]([CH:24]=1)[C:21]([NH:14][NH:13][CH:11]=[O:12])=[O:23]
Reactant: NNC=O
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(Cl)cc1C(=O)NNC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
WSC•monohydrochloride (130 mg), HOBt (110 mg) and formic hydrazide (60 mg) were sequentially added to a solution of 5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoic acid (300 mg) in DMF (6 ml), followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution, water and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure to obtain 5-chloro-N′-formyl-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzohydrazide (230 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34](Cl)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN(C=O)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][C:25]([NH:31][C:32]3[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][N:35]=[C:34]([O:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=4)[CH:33]=3)=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3cc(Cl)ncc3[N+](=O)[O-])cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(Oc2cc(Nc3ccc4c(c3)CN(C(=O)OC(C)(C)C)CC4)c([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 3-acetamidophenol (4.8 g, 32 mmol) in THF (200 mL) was cooled to 0° C. To the solution was added NaH (60% in oil, 1.3 g, 32 mol) and the mixture was warmed to rt and allowed to stir for 30 minutes. The product from Step 1 (˜8.5 g, ˜21 mmol) was added and the mixture was stirred at rt overnight then DMF (10 mL) was added and the solution was heated to 60° C. overnight. The reaction mixture was concentrated in-vacuo, then taken up in EtOAc and H2O and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude oil was purified chromatography to give the title compound (4.3 g, 39%). MS (ES+) m/e 521 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[C:34]1([C:40]2[S:41][CH:42]=[C:43](C=O)[N:44]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:43]3[N:44]=[C:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:41][CH:42]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3csc(-c4ccccc4)n3)CC1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (600 mg, 1.78 mmol, Intermediate 1) in DCM (30 ml) was treated with TEA (0.25 ml, 1.77 mmol). The pH was adjusted to 5 with AcOH and then 2-phenylthiazole-4-carbaldehyde (404 mg, 2.13 mmol) and NaBH(OAc)3 (554 mg, 2.62 mmol) were added. The mixture was stirred for 2 h at RT and then partitioned between DCM and aqueous NaHCO3 solution. The organic layer was dried over Na2SO4 and evaporated. The crude residue was purified by column chromatography (eluent: DCM/MeOH 99:1) to give (E)-3-{1′-(2-phenyl-thiazol-4-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (602 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:37]=1)[NH2:34].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:36]1[CH:37]=[C:31]([O:30][CH3:29])[CH:32]=[C:33]([NH2:34])[CH:35]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (150 mg, 0.34 mmol) were added (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (86 mg, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (27 mg, 0.03 mmol) and 340 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 87 mg (52% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16](=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=1)C>>[Cl:26][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][C:16]([OH:27])=[O:15])[CH:24]=[CH:23][C:22]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: CC(C)Sc1cccc(COc2ccc(CCC(=O)O)cc2Cl)n1
Yield: 51.9 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (41 mg, 0.20 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 59%).