Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[S:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([S:26]([N:29](CC3C=CC(OC)=CC=3OC)[C:30]3[S:31][CH:32]=[N:33][N:34]=3)(=[O:28])=[O:27])=[C:21]([F:46])[CH:20]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:25].[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:9]=2[S:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([S:26]([NH:29][C:30]3[S:31][CH:32]=[N:33][N:34]=3)(=[O:28])=[O:27])=[C:21]([F:46])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Sc3ccc(C(F)(F)F)cc3-c3ccnc(N)c3)cc2F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Nc1cc(-c2cc(C(F)(F)F)ccc2Sc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
4-{[2-(2-Aminopyridin-4-yl)-4-(trifluoromethyl)phenyl]thio}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 26, 0.153 g, 74.4 mmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) was added and the mixture stirred at room temperature under nitrogen for 3 hours. Solvents were removed in vacuo and the residue diluted in ethyl acetate (10 mL) before washing with an aqueous solution of hydrochloric acid (10 mL, 2.0 M). The organic layer was collected, dried over sodium sulphate, filtered and concentrated in vacuo. The title compound was purified by trituration in a mixture of tert-butylmethylether and dichloromethane (2:1) to give the title compound as a white solid (0.021 g, 15%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)=O)C.[OH-].[NH4+].COC1C=C(C=CC=1OC)C(O)=O.[NH2:28]C(N)=O>CO.C(OCC)(=O)C>[C:4]([C:6]1([CH3:12])[N+:10]([O-:11])=[CH:9][CH2:8][CH2:7]1)(=[O:3])[NH2:28]
Reactant: CCOC(=O)C1(C)CCC=[N+]1[O-]
Reactant: NC(N)=O
Agent: COc1ccc(C(=O)O)cc1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C(N)=O)CCC=[N+]1[O-]

Procedure:
AMPO was prepared from EMPO based on the procedure described previously with minor modification.2 A solution of 0.5 g of EMPO was mixed with 10 mL of concentrated ammonium hydroxide in a sealed tube for 5 days at room temperature with shaking. The mixture was rotary evaporated to yield a viscous dark oil and passed through a silica gel column (200-400 mesh 60 Å) twice using methanol-ethyl acetate (30:70) as solvent. White crystalline product was obtained (0.10 g, 24%), mp. 134-135° C. (lit. 137° C.)., (corrected using 3,4 dimethoxybenzoic acid, m.p., 180° C. and urea, m.p., 135° C.). 1H NMR (400 MHz, D2O) δ 1.64 (3 H, s, C(5)Me), 2.21-2.29 and 2.54-2.61 (2 H, m, C(4)H), 2.73-2.73 (2 H, m, C(3)H), 7.36 (1 H, t, C(2)H). 1H NMR (400 MHz, CDCl3) 1.90 (3 H, s, C(5)Me), 2.27-2.34 and 3.14-3.20 (2 H, m, C(4)H), 2.79 (2 H, m, C(3)H), 7.19 (1 H, t, C(2)H), 5.85 and 8.46 (2 H, br, NH2). 13C NMR (100 MHz, CDCl3) δ 24.2 (s, —CH3), 25.0 (s, C-3), 30.5 (s, C-4), 79.1 (C-5), 137.4 (C-2), 172.9 (—C═O). IR (Neat film) 1676 (C═O), 1585 (C═N), 1215 (N—O). ESI-MS calcd for C6H10N2O2Na+ m/z 165.0634, found 165.0637 amu. Anal. Calcd. for C6H10N2O2: C, 50.81; H, 7.23; N, 19.14. Found: C, 50.61; H, 7.25; N, 19.31.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=O)=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.CN(C)C=O.[OH-].[Na+]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=2)(=[O:18])=[O:19])=[CH:23][CH:22]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: OCC1CCCCN1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCCC2CSc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 57.92 g (0.504 mole) of 2-hydroxymethylpiperidine and 236 g (1.24 mole) of tosychloride in one liter of pyridine was stirred at 25° C. overnight. The mixture was quenched in water and the aqueous mixture was extracted with several portions of methylene chloride. The combined methylene chloride extract was extracted with 1M sulfuric acid solution followed by 1M aqueous sodium hydroxide, dried over magnesium sulfate and evaporated to give an oil which was shown by NMR and mass spectrometry to be 1-[(4-methylphenyl)sullfonyl[-2-piperidinemethanol ester with 4-methylbenzene sulfonic acid. A mixture of 40.78 g (0.0964 mole) of the oil, 24.60 g (0.171 mole) of p-chlorothiophenol and 25.4 g of sodium carbonate in 200 ml of dimethylformamide was stirred at 100° C. overnight and then quenced in dilute sodium hydroxide. The mixture was extracted with several portions of methylene chloride. The combined extract was extracted with several portions of 1M sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was crystallized from ether-hexane to give 29.73 g of the solid product. On standing at room temperature, the solid melted.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH:11]=O.Cl[CH2:19]CCl>O>[Br:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1/[C:11](=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH3:19]
Reactant: ClCCCl
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CC(C)(C)[S@@](N)=O
Solvent: O
Product: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(F)cc1Br
Yield: 95 %

Procedure:
Add (S)-(−)-2-methyl-2-propanesulfinamide (15 g, 73.89 mmol) to a stirring mixture of 2-bromo-4-fluorobenzaldehyde (9.85 g, 81.28 mmol) in 1,2-dichloroethane (50 mL) at RT. And then add Ti(OEt)4 (25.28 g, 4.78 mol) to the mixture and stir overnight at RT. Cool the reaction in an ice/water bath, and dilute with water. Filter the reaction mixture over a ½ inch pad of celite, and wash the filtered stuff with dichloromethane (4×150 mL). Separate the organic layer and wash the aqueous layer with 150 mL DCM. Combine the organic layers, dry over MgSO4, filter, and concentrate. Purify the residue via silica chromatography eluting with hexanes to 8:2 hexanes:ethyl acetate. Pool the desired fractions and concentrate to give the product as a very pale yellow oil (21.5 g, 95%). GCMS m/z 305 [M]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(Cl)Cl.O>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:16][CH:13]2[CH2:15][CH2:14]2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: NC1CC1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1cnc(Cl)nc1NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.25 g, 5.8 mmol) in methanol (4 mL) at 0° C. was added cyclopropylamine (0.69 mL, 10 mmol). The mixture was allowed to stir at RT for 4 h. and then DCM (20 mL) and water (20 mL) were added. The mixture was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% DCM in iso-hexane) gave 2-chloro-N-cyclopropyl-5-(trifluoromethyl)pyrimidin-4-amine (472 mg, 34%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=238 at 3.64 min. 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=1.1 Hz, 1H), 5.56 (br s, 1H), 3.03-2.93 (m, 1H), 0.99-0.89 (m, 2H), 0.65-0.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17](C)([O-:19])C.[Na+].C(OCCBr)(=O)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:16][CH2:17][OH:19])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(=O)OCCBr
Agent: [Na+]
Solvent: CS(C)=O
Product: OCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 100 mg, 0.441 mmol) in DMSO (7 mL), sodium tert-butoxide (51 mg, 0.529 mmol) and bromoethyl acetate (81 mg, 0.485 mmol) (79 mg, 66%). ESI-MS m/z [M+H]+ calc'd for C11H15ClN4O2, 271.09. found 271.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][O:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C([BH3-])#N.[Na+]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:21])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]4[CH:30]=[CH:29][C:26]5[O:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=5[N:32]=4)[CH2:7][CH2:6]3)[C:15]=2[CH:16]=1
Reactant: NC1CCN(CCN2C(=O)COc3ccc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCN4C(=O)COc5ccc(F)cc54)CC3)nc2N1
Yield: 16 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 54), (0.7 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were reacted as described under Example 21 to give 51 mg (16%) product as a solid.
Reaction SMILES: [CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:40][C:41]([F:51])([F:50])[O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([Si:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10][CH:9]([C:12]([O:14][C:46]2[CH:45]=[CH:44][C:43]([O:42][C:41]([F:40])([F:50])[F:51])=[CH:48][CH:47]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC[Si]1(c2ccccc2)CCC(C(=O)Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 78.4 %

Procedure:
A mixture of 50 g of 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylic acid, 50.0 g of triphenylphosphine and 420 ml of carbon tetrachloride was agitated under reflux for 1 hour. Then, a mixture of 32.0 g of 4-trifluoromethoxyphenol and 100 ml of pyridine was added to the mixture, followed by further addition of 1.00 g of 4-dimethylaminopyridine and agitation at room temperature for 9 hours. The resultant reaction mixture was poured into dilute hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification of the resultant residue with silica gel chromatography to obtain 60.8 g (yield: 78%) of (4-trifluoromethoxyphenyl) 4-n-pentyl-4-phenyl-4-silacyclohexanecarboxylate. The results of IR and NMR analyses are shown below.
Reaction SMILES: NC1C=CC([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][C:14](N)=[CH:13][C:11]=3[N:12]=2)=CC=1.[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[C:27]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(-c2nc3cc(N)ccc3[nH]2)cc1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Product: O=C(c1nc2ccccc2[nH]1)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Bis-trans-2-phenyl-cyclopropanecarbonyl benzimidazole was prepared by method C from 2-(4-aminophenyl)-6-amino benzimidazole (0.500 g, 2.23 mmole) and trans-2-phenyl-cyclopropanecarbonyl chloride (0.831 ml, 0.966 g, 5.35 mmole). The resulting solid was purified on silica gel (5% MeOH in CH2Cl2). HPLC showed the product was 95.5% pure.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[N:14]([CH2:21][CH:22]1[C:31]2[C:26](=[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39](=[O:41])[NH2:40])=[CH:35][N:34]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])(C)(C)C>C(Cl)Cl>[CH3:19][CH:18]([CH3:20])[CH2:17][CH2:16][CH2:15][NH:14][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH2:40])=[O:41])=[CH:35][N:34]=3)=[CH:28][CH:29]=[CH:30][C:31]1=2
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
Add TFA (540 mg, 4.73 mmol) to a solution of [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (114 mg, 0.236 mmol) and DCM (3 ml) stirring under nitrogen at ambient temperature. After 18 hours, concentrate the mixture, redissolve in EtOAc and wash with 1M aq. K2CO3, water, and brine. Dry (MgSO4), concentrate, and purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain the title compound (80 mg) as an off-white solid. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.21-7.13 (m, 2H), 6.90 (m, 2H), 6.04 (br. s, 2H), 3.01 (m, 1H), 2.90-2.79 (m, 2H), 2.68-2.55 (m, 3H), 2.49-2.41 (m, 1H), 1.84-1.64 (m, 4H), 1.57-1.46 (m, 3H), 1.19 (m, 2H), 0.87 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C>[ClH:22].[F:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:10]=[CH:9][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reactant: Clc1ncccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3Sc3ncccn3)cc2F)cn1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
To a solution of 4′-(5-aminopyrazin-2-yl)-5′-fluorobiphenyl-2-thiol (400 mg, 1.34 mmol) and 2-chloropyrimidine (167 mg, 1.47 mmol) in DMF (8 mL) were added DIPEA (345 mg, 2.68 mmol) and Ph3P (351 mg, 1.34 mmol) and the resultant mixture heated at 80° Celsius for 1 hour under a N2 atmosphere for 15 h. The mixture was cooled to rt, concentrated to dryness and the residue subjected to FCC to give the title compound (350 mg, 68%). MS (ESI): mass calcd. for C20H14FN5S.HCl, 375.10; m/z found, 376.0 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.42 (d, J=4.9, 2H), 8.33-8.28 (m, 1H), 8.03 (d, J=1.4, 1H), 7.79-7.69 (m, 2H), 7.60-7.53 (m, 1H), 7.51-7.43 (m, 2H), 7.21 (dd, J=8.0, 1.7, 1H), 7.15 (dd, J=12.3, 1.6, 1H), 7.06 (m, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH:3]1[C:18](=O)[CH2:19][CH3:20].Cl.[C:23](=[NH:26])([NH2:25])[CH3:24]>>[CH2:19]([C:18]1[C:3]2[CH2:4][NH:5][CH2:6][CH2:7][C:2]=2[N:25]=[C:23]([CH3:24])[N:26]=1)[CH3:20]
Reactant: CC(=N)N
Reactant: CCC(=O)C1CN(C(=O)OCc2ccccc2)CCC1=O
Agent: Cl
Product: CCc1nc(C)nc2c1CNCC2

Procedure:
Benzyl 4-oxo-3-propanoylpiperidine-1-carboxylate, prepared in similar manner to C28 in Example 6, was condensed with ethanimidamide hydrochloride; deprotection afforded the requisite 4-ethyl-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[C:6]=2[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[CH3:69].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH2:60][CH2:61][O:62][C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=4[CH3:69])[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:15][C:14]=3[O:26][CH3:27])[CH2:10][CH2:9][CH2:8][CH:7]([CH2:29][C:30]([N:32]3[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]3)=[O:31])[C:6]=2[CH:39]=1
Reactant: COc1cc(NC(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Reactant: Cc1ccccc1OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N(CCOc2ccccc2C)C(=O)C(F)(F)F)ccc1C(=O)N1CCCC(CC(=O)N2CCN(C)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-(2-methoxy-4-trifluoroacetylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dry tetrahydrofuran (20 ml) are added triphenylphosphine (0.54 g) and o-(2-hydroxyethoxy)toluene (0.29 g) at room temperature. To the mixture is added dropwise a solution of diethyl azodicarboxylate (0.32 ml) in dry tetrahydrofuran (5 ml), and the mixture is stirred at room temperature for 16 hours. To the mixture is added water, and the mixture is extracted with diethyl ether. The ether layer is dried, evaporated to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1→30:1) to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethyl]-1-[2-methoxy-4-{N-[2-(2-methylphenoxy)ethyl]-N-trifluoroacetylamino}benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.46 g) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH:10]([OH:12])[CH2:11]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(N2CC(O)C2)c(F)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)azetidin-3-ol (1.8 g, 9.94 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.57 g, 19.87 mmol, 2.0 eq) and phenyl chloroformate (1.71 g, 10.89 mmol, 1.1 eq) and stirred at RT for 2 h. The reaction mixture was evaporated, diluted with EtOAc (100 mL), washed with water (100 mL) followed by brine and evaporated. The residue obtained was purified by CC (eluent: EtOAc/PE (1:4)) to obtain phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (2.3 g, 76%, brown solid) (TLC: EtOAc/PE (1:1), Rf: 0.45).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11][O:12][C:13]1[CH:25]=[CH:24][C:16]([CH2:17][N:18]2[C:22]([NH2:23])=[CH:21][CH:20]=[N:19]2)=[CH:15][CH:14]=1.[CH2:26](OC(OCC)OCC)C>C(OCC)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:22]([NH:23][CH:26]=[C:5]3[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]3=[O:9])=[CH:21][CH:20]=[N:19]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Solvent: CCOCC
Product: COc1ccc(Cn2nccc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Yield: 79.1 %

Procedure:
2,2-dimethyl-1,3-dioxane-4,6-dione 1 (meldrum's acid) (20 g, 139 mmol), 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (2) (28.2 g, 139 mmol, 1 eq) (prepared according to the procedure described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. (2003), 13, 1133-1136) in presence of triethoxymethane (30.8 g, 208 mmol, 1 eq) was heated to 85° C. for 1 hr, subsequently worked up and treated with diethyl ether, and provided the pure 5-(((1-(4-methoxybenzyl)-1H-pyrazol-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3) as yellow solid (39.3 g). To a stirred solution of DOWTHERM™ (80 mL) was added compound 3 (39.3 g at 200° C. under N2 in portions over a 30 min). After completion of additions, the RM was heated at 240° C. for 1 hr. After completion of the reaction from TLC, the mixture was diluted with hexanes (300 mL) to separate the DOWTHERM™ from the crude RM. The resulting crude mixture on treatment with DCM and diethyl ether provided the off-white solid of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (4) (24.56 g). Chlorination of compound 4 (24 g, 94 mmol) on treatment with phosphoryl trichloride (43 g, 282 mmol) in dichloroethane (10 mL) at 40° C. for 4 hr yielded 19 g of 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:31][N:30]=2)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:23]3[CH2:24][CH2:25][CH:26]([C:29]4[CH:33]=[C:32]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=5)[NH:31][N:30]=4)[CH2:27][CH2:28]3)=[CH:15][CH:16]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Reaction time: 0.25 h

Procedure:
4-(6-Methoxy-4-phenylpyridazin-3-yl)benzaldehyde (2-2; 80 mg, 0.27 mmol) was dissolved in dry dimethylformamide (2 mL) and 2-(3-piperidin-4-yl-1H-pyazol-5-yl)pyridine (1-4; 99 mg, 0.43 mmol) and acetic acid (0.14 mL, 2.3 mmol) were added. After stirring for 15 min., sodium triacetoxyborohydride (116 mg, 0.54 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 hours. This reaction mixture was partially evaporated and the residue chromatographed on a silica gel column eluting with a 0-5% methanol/ethyl acetate sat'd with NH4OH. 3-methoxy-5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazine (2-3) was obtained as a nearly pure viscous oil. NMR (CDCl3): δ8.60 (1H, d, J=5 Hz), 7.69-7.72 (2H, m), 7.23-7.35 (6H, m), 7.17 (2H, br d, J=7 Hz), 6.98 (1H, s), 6.61 (1H, s), 4.22 (3H, s), 3.52 (2H, s), 2.95 (2H, d, J=12 Hz), 2.72 (1H, m), 2.10 (2H, br t, J=1 Hz), 1.97 (2H, br d, J=12 Hz), 1.81 (2H, br q, J=11).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([C:10]([O:12]C)=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1.O.O.[OH-].[Li+]>CO>[NH:1]1[C:9]2[CH2:8][CH2:7][C@H:6]([C:10]([OH:12])=[O:11])[CH2:5][C:4]=2[CH:3]=[N:2]1
Reactant: COC(=O)[C@H]1CCc2[nH]ncc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CCc2[nH]ncc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of (S)-methyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate (500 mg, 2.80 mmol) in methanol (20 mL) were added water (10 mL) and lithium hydroxide hydrate (234 mg, 5.57 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h and then concentrated to remove most of methanol. The remaining mixture was acidified with diluted aqueous HCl to pH=4 and then concentrated. The residue was dried under vacuum to afford (S)-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acid (380 mg, 81% yield) as a colorless solid, which was used directly without further purification. (R)-methyl 4,5,6,7-tetrahydro-1H-indazole-5-carboxylate was synthesized in a similar manner.