Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([NH2:37])=[C:24]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[C:31]([F:36])[CH:30]=5)[CH:25]=3)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)C.C(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]2[C:34]([CH:35]=[C:26]([C:24]3[C:23]([NH2:37])=[N:22][CH:21]=[C:20]([C:18]4[CH:17]=[N:16][N:15]([CH:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)[CH:19]=4)[CH:25]=3)[N:27]=[CH:28]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5ccc(F)cc5cn4)c3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2ccc(F)cc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
For the deprotection, 1N HCl in diethyl ether (1.0 mL) was added to a solution of 4-{4-[6-amino-5-(7-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (entire quantity isolated in the previous step) in DCM (1.0 mL) in a sealed test tube. The reaction stirred at rt for 1 h. The mixture was concentrated in vacuo to give the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.37 (4H, br.s), 3.54-3.68 (3H, m), 4.20 (1H, d, J=5.6 Hz), 4.64 (1H, br.s), 7.58-7.72 (1H, m), 7.81 (1H, br.s), 7.98 (1H, br.s), 8.06 (1H, br.s), 8.27 (2H, br.s), 8.69-8.90 (2H, m), 9.48 (1H, br.s). HPLC: tR=1.74 min. (ZQ2, polar—5 min.). MS (ES+): m/z=389.18 (95) [MH+].
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.NC1C=NC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:51]([N:54](CC)[CH:55](C)[CH3:56])([CH3:53])[CH3:52]>CN(C=O)C>[C:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([N:54]([CH2:55][CH3:56])[CH:51]([CH3:53])[CH3:52])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1)C(C)C

Procedure:
5-Cyclohex-1-enyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (15 mg, 49.8 μmol) was dissolved in DMF (5 mL) to give a light yellow solution. 3-Amino-pyridine (5.15 mg, 54.8 mmol), TBTU (24.0 mg, 74.7 μmol) and N,N-diisopropylethylamine (32.2 mg, 43.5 μA, 249 μmol) was successively added under stirring and argon to give a light brown solution. The reaction mixture was stirred for 18 h; poured into 5 mL 1N NaOH/ice water and extracted with i-propyl acetate (2×20 mL). The organic layers were combined, washed with brine (1×10 mL), dried with Na2SO4 and concentrated in vacuo to give a brown oil. The crude material was purified by preparative TLC (silica gel, 1.0 mm, n-heptane/i-propyl acetate 1:1) to give the title compound as side product (5 mg, 27%) in form of a colorless oil; LC-MS (UV peak area/ESI) 94%, 371.1936 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=O>O1CCCC1.C(OCC)C>[Cl:19][CH2:20][C:21]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Nc1ccccc1-c1cc[nH]n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: ClCc1nc2ccccc2c2ccnn12
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2.1. 8.6 g of 2-(1H-pyrazol-3-yl)aniline are dissolved in 800 ml of tetrahydrofuran. 75.3 g of potassium carbonate are added thereto, the mixture is cooled to 5° C. and then a solution of 6.7 ml of chloroacetyl chloride in 40 ml of diethyl ether is added dropwise thereto within 10 min. The mixture is stirred at 5° C. for 30 min. and then a solution of 0.67 ml of chloroacetyl chloride in 5 ml of diethyl ether is again added dropwise thereto. The mixture is stirred for a further 15 min. and then the insoluble constituent is filtered off, The filtrate is evaporated in a vacuum. The residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous phase is extracted several times with dichloromethane. The organic extracts are dried and evaporated in a vacuum. The residue is taken up in 560 ml of a 0.41N solution of hydrogen chloride in dioxan and stirred at 90° C. for 1 h. The solution is evaporated in a vacuum and the residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The dichloromethane extract is evaporated in a vacuum. 11.4 g of 5-(chloromethyl)-pyrazolo[1,5-c]quinazoline are obtained. The m.p. is 135°-136° C. after recrystallization from diisopropyl ether.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25])=[O:16].CCN(CC)CC>C(Cl)Cl>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH:14]([CH3:26])[CH2:13][CH:12]=[O:11]
Reactant: COc1ccc(C(=O)C(C)CCO)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)CC=O)c(Cl)c1
Temperature: -68 °C
Reaction time: 0.25 h

Procedure:
To a 500 mL, 3-neck round bottom flask, equipped with a mechanical stirrer and an internal thermometer, was added DMSO (17.0 mL, 239 mmol) and CH2Cl2 (200 mL). The solution was cooled to −68° C. with a dry ice/acetone bath. To this solution was added oxalyl chloride (10.4 mL, 119 mmol) slowly. The mixture was stirred at −68° C. for 15 min followed by the addition of a solution of 4-hydroxy-1-(2-chloro-4-methoxyphenyl)-2-methylbutan-1-one (12.9 g, 53.0 mmol) in CH2Cl2 (20.0 mL) slowly. After stirring at <−68° C. for 1 h, to the mixture was added Et3N (70.0 mL, 502 mmol). The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (200 mL). The aqueous layer was extracted with CH2Cl2 (2×). The combined organic solutions was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to give 8.07 g (63%) of light yellow oil as the title compound:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8](Cl)=O.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.Cl.[BH4-].[Na+]>ClC1C=CC=CC=1.COCCOCCOC.O>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([F:16])=[CH:11][C:7]=1[CH2:8][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccsc1
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: Clc1ccccc1
Solvent: COCCOCCOC
Solvent: O
Product: Fc1cc(Cc2cccs2)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
3.8 g of aluminium chloride were suspended in 162.5 ml of chlorobenzene, and a solution of 58.9 g of 2,4-dichloro-5-fluorobenzoyl chloride in 33.8 ml of chlorobenzene was added dropwise to this at 0° C. over the course of 30 minutes. The mixture was stirred at 0° C. for 90 minutes and then, at 0° C., a solution of 21.8 g of thiophene in 33.8 ml of chlorobenzene was added dropwise over the course of 30 minutes. The mixture was stirred at 0° C. for a further 2 hours and finally heated to reflux for 15 minutes until evolution of hydrogen chloride ceased. The resulting solution was added dropwise to a suspension of 7.2 g of sodium borohydride in 50 ml of diglyme at 70° C. over the course of 30 minutes, and the reaction mixture was subsequently stirred at 70° C. for 90 minutes and then discharged into a mixture of 250 g of ice, 200 ml of water and 62.5 g of concentrated aqueous hydrochloric acid. After addition of 100 ml of chlorobenzene and stirring, the phases were separated. The organic phase was extracted by shaking with 100 ml of water and was subsequently concentrated. Yield: 78.5 g of crude substance with a content of 76.7% by weight (GC) of 2-(2,4-dichloro-5-fluorobenzyl)thiophene, corresponding to 92.3% of theory. Distillation resulted in a 97.2% pure (GC) product, boiling point 140° to 145° C./8 mbar, melting point 60° to 61° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([CH3:31])[CH:33]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: Cc1cccc(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 98 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 3-methylaniline (0.038 g, 0.35 mmol), the title compound (0.113 g, 98%) was obtained.
Reaction SMILES: [C:1]1([CH3:30])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[CH:26][C:17]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[C:16]([CH3:28])[CH:15]=3)=[CH:10][C:9]=2[CH3:29])=[CH:3][CH:2]=1.[CH2:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42](I)=[CH:41][CH:40]=2)=[CH:35][CH:34]=1)[CH3:32]>>[C:1]1([CH3:30])[CH:2]=[CH:3][C:4]([N:7]([C:42]2[CH:43]=[CH:44][C:39]([C:36]3[CH:37]=[CH:38][C:33]([CH2:31][CH3:32])=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[CH:26][C:17]([N:18]([C:4]4[CH:5]=[CH:6][C:1]([CH3:30])=[CH:2][CH:3]=4)[C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=5)=[CH:21][CH:20]=4)=[C:16]([CH3:28])[CH:15]=3)=[CH:10][C:9]=2[CH3:29])=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2ccc(-c3ccc(Nc4ccc(C)cc4)c(C)c3)cc2C)cc1
Reactant: CCc1ccc(-c2ccc(I)cc2)cc1
Product: CCc1ccc(-c2ccc(N(c3ccc(C)cc3)c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc(-c6ccc(CC)cc6)cc5)c(C)c4)cc3C)cc2)cc1
Yield: 23.7 %

Procedure:
According to the same manner as that described in Synthesis Example 1, 14.9 g of N,N'-diacetyl-3,3'-dimethylbenzidine was reacted with 21.8 g of para-iodobenzene to give N,N'-di-p-tolyl-3,3'-dimethylbenzidine. Further, 12.0 g of N,N'-di-p-tolyl-3,3'-dimethylbenzidine was reacted with 15.4 g of 4-ethyl-4'-iodobiphenyl according to the same manner as that described in Synthesis Example 1 to give N,N'-di-p-tolyl-N,N'-di(4'-ethylbiphenyl-4-yl)-3,3'-dimethylbenzidine (hereinafter referred to as 6-c) (8.82 g, yield: 23.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[NH2:25])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][C:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH3:10])[CH3:9])=[O:26])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.2 %

Procedure:
A mixture of tert-butyl[1-[3-(2-amino-5-chlorophenoxy)phenyl]-1-methylethyl]carbamate (2.5 g, 6.62 mmols), ethyl 4-bromobutyrate (9.0 g, 46 mmols), potassium carbonate (2.7 g, 20 mmols) and N,N-dimethylformamide (20 ml) was stirred at 80° C. for 24 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-(1-tert-butoxycarbonylamino-1-methylethyl)phenoxy]-4-chlorophenyl]]aminobutyrate (1.6 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][C@H:24]([OH:32])[CH2:25][N:26]5CC[C@@H:28]([F:31])[CH2:27]5)[C:18]4=[O:33])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:36]([F:39])([F:38])[F:37])[CH:3]=1.FCCN>>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[N:19]([CH2:23][C@H:24]([OH:32])[CH2:25][NH:26][CH2:27][CH2:28][F:31])[C:18]4=[O:33])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:36]([F:38])([F:37])[F:39])[CH:3]=1
Reactant: O=C1SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H](O)CN1CC[C@@H](F)C1
Agent: NCCF
Product: O=C1SC(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H](O)CNCCF

Procedure:
5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-[(2R)-3-(2-fluoroethylamino)-2-hydroxypropyl]thiazolidine-2,4-dione was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-3-(S)-oxiranylmethylthiazolidine-2,4-dione (from Example 294) and 2-fluoroethylamine following General Procedure X.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[N:11]=[C:12]=[O:13]>O1CCCC1>[CH3:8][C:9]([CH3:19])([CH3:18])[C@@H:10]([C:14]([O:16][CH3:17])=[O:15])[NH:11][C:12]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:13]
Reactant: COC(=O)[C@@H](N=C=O)C(C)(C)C
Reactant: C=CCCCNC
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)(C)C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of N-methylpent-4-en-1-amine (2.0 g, 20.2 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature under nitrogen. To this was added methyl 3-methyl-N-(oxomethylene)-L-valinate (3.5 g, 20.2 mmol) and the resulting solution stirred 2 h. Contents of the reaction flask were evaporated and subjected to flash column chromatography eluting with hexane/ethyl acetate 60/40 to give methyl 3-Methyl-N-{[methyl(pent-4-enyl)amino]carbonyl}-L-valinate as an orange oil, 3.02 g (55% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([N:14]2[C:19]3=[N:20][CH:21]=[N:22][C:18]3=[CH:17][N:16]([OH:23])[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[N+](C1C=CC(N=C=O)=CC=1)([O-])=O.[O:36]([C:43]1[CH:48]=[CH:47][C:46]([N:49]=C=O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[O:36]([C:43]1[CH:44]=[CH:45][C:46]([NH:49][C:6]([N:8]2[CH2:9][CH2:10][N:11]([N:14]3[C:19]4=[N:20][CH:21]=[N:22][C:18]4=[CH:17][N:16]([OH:23])[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(N2CN(O)C=C3N=CN=C32)CC1
Agent: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)N1CCN(N2CN(O)C=C3N=CN=C32)CC1

Procedure:
The target compound was produced in the same manner as in Example 2, except that 4-(6-purinyl)-1-piperazinecarboxylic acid tert-butyl ester was replaced with 4-(6-hydroxy-4-imidazo[4, 5-d]pyrimidinyl )-1-piperazinecarboxylic acid tert-butyl ester produced in Reference Example 11, and that 4-nitrophenyl isocyanate was replaced with 4-phenoxyphenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[C:12]([NH2:13])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:16]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([NH:13][CH3:16])=[N:11][N:10]=[N:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nnnc2N)cc1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1nnnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Next, to a suspension of 1-(4-methoxy-benzyl)-1H-tetrazol-5-ylamine (600 mg, 2.92 mmol) in MeOH (10 mL) were added paraformaldehyde (132 mg, 4.39 mmol) and sodium methoxide (632 mg, 25 wt % in MeOH). The mixture was refluxed for 30 min until the suspension turned into a clear solution. The mixture was cooled to room temperature and sodium borohydride (332 mg, 8.77 mmol) was added portionwise. The reaction mixture was refluxed again for 15 min. After cooled to room temperature, the reaction was quenched with H2O. The mixture was diluted with EtOAc, partially concentrated, and washed with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give [1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-amine (0.63 g). 1H NMR (400 MHz, CDCl3) δ 3.00 (d, 3H, J=5.3 Hz), 3.61 (bs, 1H), 3.82 (s, 3H), 5.25 (s, 2H), 6.91 (d, 2H, J=8.8 Hz), 7.16 (d, 2H, J=8.8 Hz); MS: m/z (MH+) 220.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>CO.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: O=[Pt]=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2Br)CC1
Reaction time: 4 h
Yield: 56.7 %

Procedure:
A solution of tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate J, 8.45 g, 20.80 mmol) and platinum(IV) oxide (0.472 g, 2.080 mmol) in 40 mL MeOH was placed under 45 psi (4559.6 kpa) H2 for 2 hours. The reaction mixture was filtered through a plug of diatomaceous earth and was concentrated. The resulting residue was taken up in 10 mL THF, was treated with di-tert-butyl dicarbonate (10.40 ml, 10.40 mmol) followed by triethylamine (2.90 ml, 20.80 mmol) and was allowed to stir for 4 hours. Concentration and purification of the resulting residue by silica gel column chromatography (0 to 10% EtOAc/heptane) gave tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate (4.812 g, 11.79 mmol) as a clear oil. [M+Na]+=432.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH2:29])=[CH:23][NH:24]2)=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([CH2:27][CH2:28][NH:29][C:11]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]4[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=4)[O:10][N:9]=3)=[O:13])=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2cc(F)ccc12)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A mixture of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-fluoro-1H-indol-3-yl)ethanamine (0.051 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisoprpylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.040 g (41%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][CH3:12])=[N:7][C:6]=2[C:5]([N+:13]([O-])=O)=[C:4]([F:16])[CH:3]=1>[Pd].C(OCC)(=O)C.[H][H]>[NH2:13][C:5]1[C:6]2[N:7]=[C:8]([CH2:11][CH3:12])[O:9][C:10]=2[C:2]([Cl:1])=[CH:3][C:4]=1[F:16]
Reactant: [H][H]
Reactant: CCc1nc2c([N+](=O)[O-])c(F)cc(Cl)c2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1nc2c(N)c(F)cc(Cl)c2o1
Yield: 96.7 %

Procedure:
Step 5 Palladium on activated carbon (10%, 0.1 g) was added to a solution of 7-chloro-2-ethyl-5-fluoro-4-nitrobenzoxazole (0.86 g) in ethyl acetate (80 ml) and hydrogen was bubbled through the suspension for 5 hours. After filtration and evaporation, 4-amino-7-chloro-2-ethyl-5-fluorobenzoxazole(0.73 g) was obtained as the single product.
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[F:47][CH:48]([F:77])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[NH:58][CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1>CN(C=O)C>[F:77][CH:48]([F:47])[CH2:49][NH:50][C:51]1[N:56]=[C:55]2[CH:57]([CH3:61])[N:58]([C:3](=[O:4])[CH:2]([F:6])[F:1])[CH2:59][CH2:60][C:54]2=[N:53][C:52]=1[N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][C:72]([F:75])=[CH:71][C:70]=2[F:76])[CH2:64][CH2:63]1
Reactant: O=C(O)C(F)F
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1c2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CCN1C(=O)C(F)F
Reaction time: 8 h

Procedure:
A solution of 2,2-difluoroacetic acid (2.86 mg, 0.030 mmol), HATU (11.3 mg, 0.030 mmol), and DIPEA (14.2 μL, 0.081 mmol) in DMF (136 μL) was stirred at room temperature for 10 min. Then, N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol) was added and stirring was continued overnight. No desired product was detected by LCMS. To this was added 2,2-difluoroacetic anhydride (7.08 mg, 0.041 mmol) and after 1 h, purification by HPLC Method A afforded the title compound as a TFA salt (4.4 mg) as an off-white film. 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.51 (d, J=6.8 Hz, 2.1H), 1.62 (d, J=6.8 Hz, 0.9H), 1.94-2.02 (m, 2H), 2.10-2.18 (m, 2H), 2.68-2.78 (m, 1H), 2.82-3.06 (m, 3.2H), 3.36-3.44 (m, 2H), 3.53-3.61 (m, 0.7H), 3.71-3.88 (m, 2.1H), 4.16 (dd, J=14.2, 5.4 Hz, 0.7H), 4.46 (dt, J=7.4, 3.8 Hz, 1H), 4.67 (dd, J=13.2, 5.9 Hz, 0.3H), 4.97 (q, J=6.7 Hz, 0.3H), 5.27 (q, J=6.8 Hz, 0.7H), 5.93-6.20 (m, 1H), 6.43-6.70 (m, 1H), 6.85-6.92 (m, 1H), 6.99 (ddd, J=11.3, 8.4, 3.2 Hz, 1H), 7.18 (td, J=9.3, 5.4 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.