Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][Si](C=[N+]=[N-])(C)C>C1COCC1.C(OCC)(=O)C>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-2-nitro-benzoic acid (1 g, 5.4 mmol in 5 mL THF, was added (trimethylsilyl)diazomethane (2 M in ether, 11 ml, 22 mmol) at 0° C. The reaction mixture was warmed to room temperature under argon and stirred for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-30% EtOAc/hexane) to give 5-fluoro-2-nitro-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:21][NH2:22]>C(O)C>[NH2:2][C:1]1[NH:22][N:21]=[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NN
Reactant: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C(N)=O
Solvent: CCO
Solvent: O
Product: NC(=O)c1c(Nc2ccc([N+](=O)[O-])cc2)n[nH]c1N
Temperature: 75 °C

Procedure:
2-cyano-3-(methylthio)-3-((4-nitrophenyl)amino)acrylamide was then suspended in 100 mL of ethanol and hydrazine hydrate (5.153 mL, 2.00 eq.) was added drop wise to the reaction. The reaction was then heated at 75° C. until the starting material was no longer present as confirmed via HPLC. Once starting material was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-nitrophenyl)amino)-1H-pyrazole-4-carboxamide as an off white to yellow powder as product. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Solvent: ClCCl
Product: CCCCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 86.3 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.10 g, 0.46 mmol), heptanoyl chloride (0.072 mL, 0.46 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (12 mL) provided N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylheptanamide (0.13 g). MS m/z 328 ([M+H]+); HRMS: calcd for C21H29NO2+H+, 328.22710; found (ESI, [M+H]+), 328.2263.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[CH:17]=2)=[O:13])[CH:9]=[C:8]([Cl:24])[C:3]=1[C:4]([O:6]C)=[O:5].C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:13])[CH:9]=[C:8]([Cl:24])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(C(=O)NCc2cccc(OC)c2)cc1Cl
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reaction time: 3 h
Yield: 80 %

Procedure:
A suspension of 2,6-dichloro-4-[[(3-methoxybenzyl)amino]carbonyl]benzoic acid, methyl ester (11.83 g, 32.1 mmol) in dichloromethane (400 mL) was cooled to ˜−78° C. (dry ice-acetone bath) and boron tribromide (1M in dichloromethane; 100 mL, 100 mmol) was added. The mixture was stirred in the cooling bath for 3 h and then allowed to stand at room temperature for 72 h. The supernatant was decanted off and water (300 mL) was added to each of the supernatant and the residue. The mixtures were stirred at ˜40° C. for 1 h and then the solids were collected by filtration, combined and air-dried to give 2,6-dichloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoic acid (8.73 g, 80% yield) as a cream-colored solid.
Reaction SMILES: C(C[C:4]1[CH:5]=[CH:6][C:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](=[O:17])[C:8]=2[CH:18]=1)#N.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[O:17]=[C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[O:16][C:7]2[CH:6]=[CH:5][C:4]([CH2:20][C:19]([OH:22])=[O:21])=[CH:18][C:8]1=2
Reactant: N#CCc1ccc2oc3ncccc3c(=O)c2c1
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A solution of 12 g of 7-cyanomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine in a mixture of 60 ml of acetic acid and 25 ml of concentrated hydrochloric acid is heated under reflux on an oil bath for 24 hours. After concentration, water is added to the residue, and further a 10% sodium hydroxide solution is added to dissolve the residue. An insoluble material is removed by extraction with chloroform. The aqueous layer is made acid with acetic acid, and the resulting crystalline precipitate is filtered off and recrystallized from aqueous dimethylformamide to give 8.6 g of 5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl-acetic acid as white needles melting at 244°- 245°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[OH:8])[CH2:3][CH2:2]1.[O:29]=[C:30]1[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][N:31]1[CH2:47][C:48](O)=[O:49].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH:4]1[CH2:5][CH2:6][N:1]([C:48](=[O:49])[CH2:47][N:31]2[CH2:32][CH2:33][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:30]2=[O:29])[CH2:2][CH2:3]1
Reactant: OC(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)C1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidin-4-ylbis(3-(trifluoromethyl)phenyl)methanol (0.40 mg, 1.00 mmol, Example 33A) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85-7.93 (m, 4H), 7.55-7.57 (m, 4H), 7.18-7.36 (m, 10H), 5.93 (s, 1H), 4.34-4.41 (m, 1H), 4.06-4.23 (m, 2H), 3.82 (d, J=13.5 Hz, 1H), 3.35 (t, J=6.9 Hz, 2H), 2.94-3.11 (m, 2H), 2.72 (t, J=6.4 Hz, 2H), 2.59-2.67 (m, 1H), 1.17-1.50 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Solvent: CCO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Yield: 99.3 %

Procedure:
A solution of 4-nitro-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (185 mg, 0.45 mmol) in 10 mL of ethanol was hydrogenated at atmospheric pressure over 47 mg of 10% Pd(C) for 3 hours. The reaction mixture was filtered through a pad of celite and evaporated to dryness to give 4-amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (170 mg, 99%) of as a white solid suitable for use in the next step.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH2:22])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:36][N:33]1[CH2:34][CH2:35][N:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:22][C:20]3[N:21]=[C:14]4[C:13]([C:10]5[CH:11]=[CH:12][C:7]([S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:8][CH:9]=5)=[CH:18][CH:17]=[CH:16][N:15]4[N:19]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)S(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc(N5CCN(C)CC5)cc4)nc23)cc1

Procedure:
8-[4-(Propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500.0 mg, 2.347 mmol) and 4-isopropylsulfonylbenzeneboronic acid (650.0 mg, 2.850 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.317 g, 42%). MP=175-177° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.64 (d, J=6.6 Hz, 1H), 8.39 (d, J=7.4 Hz, 2H), 7.96 (d, J=7.5 Hz, 2H), 7.85 (d, J=7.4 Hz, 1H), 7.06-7.00 (m, 1H), 6.21 (br s, 2H), 3.54-3.42 (m, 1H), 1.19 (d, J=6.5 Hz, 6H). MS=317 (MH)+. 52b) [4-(4-Methyl-piperazin-1-yl)-phenyl]-{8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amine was prepared from 8-[4-(propane-2-sulfonyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.237 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0877 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.051 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.7 Hz, 1H), 8.25 (d, J=7.8 Hz, 2H), 8.02 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.49 (d, J=7.8 HZ, 2H), 7.01-6.95 (m, 3H), 6.69 (s, 1H), 3.30-3.15 (m, 5H), 2.63-2.58 (m, 4H), 2.36 (s, 3H), 1.36 (d, J=6.7 Hz, 6H). MS=491 (MH)+.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]2[C:6]=1[C:7]([NH2:8])=[N:2][NH:3]2
Reactant: NN
Reactant: N#Cc1c(F)cccc1I
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2cccc(I)c12
Temperature: 78 °C

Procedure:
1.2 cm3 of hydrazine monohydrate are added to 2 g of 2-fluoro-6-iodobenzonitrile in 25 cm3 of ethanol. The reaction medium is then refluxed at about 78° C. for 12 hours. The medium is allowed to return to about 20° C. and 20 cm 3 of distilled water are then added in order to precipitate the product. The insoluble material is filtered on a sinter funnel, rinsed with 20 cm3 of distilled water and then taken up in 20 cm3 of dichloromethane. The organic phase is then dried over magnesium sulphate and evaporated under reduced pressure (2 kPa; 45° C.). After drying (90 Pa; 50° C.), 1.65 g of 4-iodo-1H-indazole-3-amine are obtained in the form of a yellow solid melting at 157° C.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:49])[N:42]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH:43]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:39]=[CH:40][C:41](=[O:49])[N:42]([CH2:44][C:45]([F:47])([F:48])[F:46])[CH:43]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1ccc(Br)cn1CC(F)(F)F
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(CC(F)(F)F)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 5-bromo-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.323 min, m/z=471.1; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.19-2.30 (m, 4H), 2.40 (m, 1H), 2.89 (m, 1H), 4.67 (m, 2H), 5.69 (m, 1H), 6.70 (d, 1H), 7.03 (d, 2H), 7.13 (d, 2H), 7.29-7.38 (m, 6H), 7.55 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].C(OCC)(=O)C>CO>[NH2:25][C:23](=[O:24])[CH2:22][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:26])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1
Reactant: COC(=O)COc1cccc2c1c(CC(N)=O)cn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)Cc1cn(Cc2ccccc2)c2cccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester and 2 mL of 1N NaOH in 6 mL of MeOH was stirred at room temperature for 2 hours. Hater and ethyl acetate were added and the aqueous layer separated, made acidic to pH 3 with 1N HCl and ethyl acetate added. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was stirred with methylene chloride and filtered to give 17 mg (56% yield) of 2-[[3-(2-amino-2-oxoethyl)-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, mp, 207-208° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1>C(#N)C.ClCCl>[CH:7]1([CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:16]=[N:17][C:18]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:19][CH:20]=2)=[O:14])[CH2:9][CH2:8]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CC#N
Product: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Yield: 74.8 %

Procedure:
A mixture of piperazine (1.48 g, 17.2 mmol) and 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (1.29 g, 5.73 mmol) in acetonitrile (60 mL) was heated at reflux for 16 hours. After the reaction mixture was cooled, the gummy material was diluted with dichloromethane (50 mL), washed with water (2×20 mL), dried over MgSO4. After filtration, the filtrate was concentrated in vacuo. The crude material was purified by column chromatography eluting with dichloromethane (100%) then with methanol:dichloromethane (1:9) to obtain 1.18 g (75%) of the product as a solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2[C:13]([O:15]C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]O.[OH-].[K+]>O>[CH3:23][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CO
Reactant: COC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of methyl 3,5-diphenylpyridazine-4-carboxylate (300 mg, 1.03 mmol) in 1:1 MeOH:H2O (10 mL), KOH (576 mg, 10.28 mmol) was added and refluxed at 100° C. for 12 h. After the completion of starting material, the reaction mixture was diluted with water (5 mL×1) and washed with ethyl acetate (5 mL×1). The aqueous layer was acidified with 6N HCl (5 mL) solution, solid precipitated out. The solid was filtered and dried to furnish methyl 3, 5-diphenylpyridazine-4-carboxylic acid (compound 6) (275 mg, 96%) as a white solid.
Reaction SMILES: FC1N=C([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])=[N:10]2)C=CC=1.BrC[C:27]1[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:33][C:28]1[C:27]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])=[N:10]2)=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccc(F)n2)n1
Reactant: Fc1ncccc1CBr
Product: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccnc2F)n1
Yield: 62.3 %

Procedure:
Title compound was prepared by a method analogous to that described for Intermediate 45, replacing 2-(chloromethyl)-6-fluoropyridine with Intermediate 13 (200 mg, 1.051 mmol) to yield the title compound (211 mg, 0.655 mmol, 62.3% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.21 (m, 1H), 8.00 (d, 1H), 7.95-7.88 (m, 4H), 7.78 (m, 1H), 7.38 (m, 1H), 6.41 (d, 1H), 5.46 (s, 2H). [ES+MS] m/z 323 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:11]([C:12](OC)=[O:13])=[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([C:24]([O:26][CH3:27])=[O:25])=[N:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:17]([O:16][C:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[N:8][N:7]2[CH2:6][CH2:5][CH2:4][NH:1][C:12](=[O:13])[C:11]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nn(CCCN=[N+]=[N-])c(C(=O)OC)c1OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 1-(3-azidopropyl)-4-benzyloxy-1H-pyrazole-3,5-dicarboxylate (152 mg, 0.407 mmol) in THF (2 mL) were added triphenylphosphine (107 mg, 0.407 mmol) and water (37 μL, 2.036 mmol). The reaction was stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was dissolved in toluene and heated to 110° C. overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.44-7.41 (m, 2H), 7.34-7.28 (m, 3H), 6.70 (br s, 1H), 5.29 (s, 2H), 4.46-4.42 (t, 2H), 3.96 (s, 3H), 3.06-3.00 (m, 2H), 2.20-2.13 (m, 2H); ES MS (M+1)=316.
Reaction SMILES: C(=O)=O.CC(C)=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:11]=2[CH:10]=1.CC([O-])(C)C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH3:27])[C:14](=[O:26])[CH:15]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:16]=[C:17]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: Cc1ccccc1CBr
Reactant: COc1ccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(C2=NC(Cc3ccccc3C)C(=O)N(C)c3ccc(Cl)cc32)cc1
Yield: 84.1 %

Procedure:
To a stirred and cooled (dry ice/acetone bath) solution of E1 (0.50 g, 1.59 mmol) in THF (8 mL) was slowly added 1 M KOtBu (2.4 mL, 2.4 mmol, 1.5 eq). The resulting deep red mixture was stirred over dry ice/acetone bath ˜10 min followed by the slow addition of a solution of 2-methylbenzyl bromide (0.46 g, 2.5 mmol, 1.5 eq) in THF (2 mL). After stirring another ˜35 min at −78° C., the reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated (rotovap, then high vacuum). Chromatography over silica gel using 20-40% EtOAc/heptane gave 0.56 g (yield of 84%) of the title product. Noting that, when using benzyl chlorides as alkylating agents, tetrabutyl ammonium iodide was added along with the alkylating agent at the low temperature. 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 3.41 (s, 3H), 3.5-3.65 (m, 2H), 3.74 (dd, 1H), 3.84 (s, 3H), 6.89 (dt, 2H), 7.05-7.15 (m, 3H), 7.25-7.35 (m, 3H), 7.45-7.5 (m, 3H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:23]=[C:22]([Cl:21])[CH:28]=[C:27]([Cl:29])[CH:26]=2)=[O:13])[CH:26]=[C:27]([Cl:29])[CH:28]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 22.5 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3,5-dichloroaniline (1.87 g, 11.7 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.78 g of the title compound, mp 235-236° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15](=O)[CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:24][C:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[NH:38])=[CH:32][CH:31]=2)[CH:27]=[CH:28][N:29]=1>>[CH3:24][C:25]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37]3[N:38]=[C:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:3]4[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7][C:2]=4[N:39]=3)=[CH:34][CH:35]=2)[CH:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)CC2CCOCC2)C1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 86 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (745 mg, 86%) was synthesised from tert-butyl 4-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)acetyl)piperidine-1-carboxylate and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES−) m/z 503.3 (M−H)−
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:30][C:29]4[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:28]=4[Cl:27])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3c(F)cccc3Cl)nc2)c2cccnc21

Procedure:
5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 30 mg, 0.083 mmol, prepared as described in Example 68, Scheme 185) was combined with 2-chloro-6-fluoro-benzaldehyde (616, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give compound 617, which was used in the next step without further purification.