Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[Cl:38][C:39]1[CH:40]=[C:41]([CH3:48])[C:42]([C:45](O)=[O:46])=[N:43][CH:44]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:45](=[O:46])[C:42]3[C:41]([CH3:48])=[CH:40][C:39]([Cl:38])=[CH:44][N:43]=3)[CH:3]=[CH:4][C:5]=2[F:28])([CH3:27])[N:9]=1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(Cl)cnc1C(=O)O
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A round-bottomed flask was charged with N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (rac-4l, 0.233 g, 0.589 mmol), DCM (8 mL), N,N-diisopropylethylamine (0.133 mL, 0.766 mmol), 5-chloro-3-methylpicolinic acid (intermediate 6) 0.131 g, 0.766 mmol) and finally with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.347 mL, 0.589 mmol). The reaction mixture was stirred at room temperature for 15 min. The Reaction mixture was poured into aqueous saturated NaHCO3 (50 mL) and then extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over Na2SO4 and loaded onto silica gel. Purification by silica gel chromatography (gradient 0 to 30% EtOAc/hexane) gave the title compound (50 mg). MS m/z=549.1 [M+H]+. Calculated for C26H21ClF4N4O3: 548.9
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:3]1=2.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:17]1([C:15]2[S:14][C:4]3[N:5]=[C:6]4[CH:11]=[CH:10][C:9]([C:12]5[NH:25][N:24]=[N:23][N:13]=5)=[CH:8][N:7]4[C:2](=[O:1])[C:3]=3[CH:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1c2cc(-c3ccccc3)sc2nc2ccc(-c3nnn[nH]3)cn12
Temperature: 0 °C
Yield: 31.8 %

Procedure:
A mixture of 1.5 g (0.005 mol) of 4-oxo-2-phenyl-4H-pyrido-[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 31), 1.0 g (0.0153 mol) of sodium azide and 0.9 g (0.0168 mol) of ammonium chloride in 200 ml of dimethylformamide is heated at 110°-120° C. for three days. The reaction mixture is cooled, poured into 1 l of ice water and acidified with concentrated hydrochloric acid. The resulting precipitate is filtered and dissolved in hot pyridine, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.55 g of 2-phenyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 310°-312° C. (dec) after recrystallization from pyridine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:26]=[C:25]([NH2:27])[N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:27][C:25]1[N:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:34])=[CH:16][CH:17]=2)[N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3nc(N)n(-c4ccccn4)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(Nc2ccc(C(=O)N3CCNCC3)cc2)nn1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 4-[4-(5-amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (22.1 mg) and trifluoroacetic acid (0.50 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the title compound (13.6 mg) as a white solid. MS (ES+): m/z=365.1; 1H NMR (CD3SOCD3, 500 MHz): δ 3.09-3.23 (m, 4H), 3.63-3.76 (m, 4H), 7.20-7.25 (m, 1H), 7.41 (d, 2H), 7.64-7.74 (m, 4H), 7.95-8.02 (m, 1H), 8.39-8.44 (m, 1H), 8.66-8.95 (m, 2H), 9.44-9.48 (m, 1H).
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Br:22][C:23]1[CH:24]=[C:25]([N:12]2[CH2:13][CH2:14][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:11]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1cccc(Br)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed copper(I) iodide (1.0 g, 5.26 mmol, 0.20 equiv), L-proline (930 mg, 8.09 mmol, 0.30 equiv) in DMSO (50 mL). The resulting solution was stirred for 15 min at room temperature. Then, tert-butyl piperazine-1-carboxylate (5 g, 26.88 mmol, 1.00 equiv), 1,3-dibromobenzene (9.5 g, 40.25 mmol, 1.50 equiv), potassium carbonate (7.4 g, 53.62 mmol, 1.99 equiv) was added. The resulting solution was stirred overnight at 90° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 2.9 g of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)CCCc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCc1ccccc1

Procedure:
Following General Procedure B′ and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Cl:1]C(C1C=CC=CN=1)(Cl)Cl.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:14][C:13]=1C(Cl)(Cl)Cl.ClCl>>[Cl:1][C:13]1[CH:14]=[C:15]([C:18]([Cl:21])([Cl:20])[Cl:19])[CH:16]=[N:17][C:12]=1[Cl:11]
Reactant: Clc1ncc(C(Cl)(Cl)Cl)cc1C(Cl)(Cl)Cl
Reactant: ClC(Cl)(Cl)c1ccccn1
Agent: ClCl
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
Seventy-five grams of a mixture containing 24.3% 3,5-bis(trichloromethyl pyridine and 6.5% 6-chloro-3,5-bis(trichloromethyl)pyridine were chlorinated with 70 grams per hour of chlorine at 190° C. for 8 hours. Analysis is listed in Table 8. The 5,6-dichloro-3-trichloromethyl pyridine concentration went from zero to 0.5% and the 2,6-dichloro-3,5-bis(trichloromethyl)pyridine went from zero to 0.7%. The 3,5-bis(trichloromethyl)pyridine went from 24.3% to 18.1% while the 6-chloro-3,5-bis(trichloromethyl)pyridine increased from 6.5% to 14.0%. Temperatures below 190° C. give unacceptably slow reaction rates to produce 5,6-dichloro-3-trichloromethyl pyridine and 2,3,5,6-tetrachloropyriidine.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@@H:23]([CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][C:27]1[N:28]=[CH:29][NH:30][CH:31]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N[C@H](CO)Cc1c[nH]cn1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@H](CO)Cc3c[nH]cn3)cc2c1=O
Yield: 46 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (S)-2-amino-3-(1H-imidazol-4-yl)-propan-1-ol according to the GPA affording 24.1 mg (46%) of a red powder. Rt=1.73 min.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([CH3:5])[C:3]#[CH:4].[C:7]([NH:12][C:13]1[CH:14]=[C:15]([O:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1)([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:10]([O:9][C:7](=[O:8])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20](=[O:21])[NH:6][C:2]([CH3:5])([CH3:1])[C:3]#[CH:4])[CH:14]=1)[CH3:11]
Reactant: C#CC(C)(C)N
Reactant: CCOC(=O)Nc1cccc(OC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CC(C)(C)NC(=O)Oc1cccc(NC(=O)OCC)c1
Reaction time: 0.5 h

Procedure:
Into a solution of 5.0 g (0.06 mole) of 1,1-dimethypropinylamine in 30 ml acetic ester is dropped, after addition of 50 ml water, at 10° to 15° C., while stirring, a solution of 14.6 g (0.06 mole) chloroformic acid-3-(N-carbethoxyamino)-phenyl ester in 30 ml acetic ester and simultaneously a solution of 8.3 g (0.06 mole) potassium carbonate in 30 ml water, the reaction product crystallizing out. Stirring is continued for 30 minutes while cooling with ice. The product is suction-filtered and washed with ether and water.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.[NH2:10][C@@H:11]([CH3:29])[CH2:12][N:13]1[CH:17]=[C:16]([C:18]#[N:19])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[CH:21]=2)=[N:14]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:15]2[C:16]([C:18]#[N:19])=[CH:17][N:13]([CH2:12][C@@H:11]([NH:10][C:7]([C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)=[O:9])[CH3:29])[N:14]=2)[CH:25]=[CH:24][C:23]=1[C:26]#[N:27]
Reactant: Cn1cnc(C(=O)O)c1
Reactant: C[C@H](N)Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1cc(C#N)c(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(C)cn1
Yield: 34.1 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 1-methyl-1H-imidazole-4-carboxylic acid (53.0 mg, 0.420 mmol) and (S)-1-(2-aminopropyl)-3-(3-chloro-4-cyanophenyl)-1H-pyrazole-4-carbonitrile (100 mg, 0.350 mmol). The product was purified by recrystallization from diethyl ether and diethyl ether/ethanol, respectively. Finally the product was also run through flash chromatography. Yield 34.1%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 3.67 (s, 3H), 4.36-4.51 (m, 3H), 7.56 (d, 1H), 7.69 (d, 1H), 7.98 (dd, 1H), 8.04-8.10 (m, 2H), 8.15 (dd, 1H), 8.69 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:18])[C:5]2[C:13](=[CH:14][C:15]=1[O:16]C)[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:4](=[O:18])[C:5]2[C:13](=[CH:14][C:15]=1[OH:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2
Reactant: COC1=C(OC)C(=O)C2=Cc3ccccc3C2=C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1C2=Cc3ccccc3C2=CC(O)=C1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,3-Dimethoxyfluorenone (15 g) was dissolved in toluene (300 ml), to which was added anhydrous aluminum chloride (20 g) and the mixture was stirred at 90° C. for 2 hours. After cooling, the reaction solution was poured into ice water (1.5 liter). Then, the insoluble matter formed was filtered, washed with water, dried and recrystallized from ethyl acetate to give 9.8 g of 2,3-dihydroxyfluorenone as a yellow needle-like crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([CH2:13][CH2:14][F:15])[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19].[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][NH:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH2:24][C@@H:25]2[C@H:29]([F:30])[CH2:28][N:27]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:19])[C:6]([C:16]([OH:18])=[O:17])=[CH:7][N:8]4[CH2:13][CH2:14][F:15])=[CH:3][C:2]=3[F:1])[CH2:26]2)[CH2:22][CH2:21]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: O=C(O)c1cn(CCF)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(CCF)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 45.5 %

Procedure:
Using 6,7-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (271 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (186 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[N:3]1.O[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][O:9][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1CCO
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1CCOc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.6 %

Procedure:
A mixture of 2-(1-methyl-1H-pyrazol-5-yl)ethanol (1.00 g), 4-hydroxybenzotrifluoride (2.57 g), 1.9 M diisopropyl azodicarboxylate (6.26 mL, toluene solution), triphenylphosphine (3.12 g) and tetrahydrofuran (50 mL) was stirred at a room temperature for 2 days. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=90:10 to 55:45), so as to obtain the title compound (1.17 g) in the form of a light yellow oily substance.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[OH:36][CH2:37][CH:38]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH2:38][CH2:37][OH:36])[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=CCO
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(CCO)C2(CC2)C1
Reaction time: 12 h

Procedure:
A solution of N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8 (0.05 mmol), 2-hydroxyacetaldehyde (0.6 mmol) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D10. 1H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.95 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.89 (m, 2H), 2.77 (m, 2H), 2.54 (m, 2H), 2.51 (m, 4H), 2.10 (s, 3H), 0.50-0.62 (m, 4H). MS (m/z) (M+1)+: 525.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=1.[OH:19][CH:20]([C:33]1[CH:38]=[CH:37][C:36](/[C:39](=[N:41]\O)/[NH2:40])=[CH:35][CH:34]=1)[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.C(OCC)(=O)C>[OH:19][CH:20]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:41]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:40]=2)=[CH:35][CH:34]=1)[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][C@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1
Reactant: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(/C(N)=N\O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-IV (45 mg, 0.174 mmol), (3S)-ethyl 1-(2-hydroxy-2-(4-((E)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (70 mg, 0.209 mmol), and BOP-Cl (53 mg, 0.208 mmol) in DMF (5 mL) was added TEA (0.073 mL, 0.523 mmol). The reaction mixture was stirred at room temperature for 2 hr then TBAF (0.174 mL, 0.174 mmol) was added. Next, the reaction mixture was stirred for 3 days. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO4, filtered, and concentrated. The crude residue was purified by a silica gel cartridge using an EtOAc/hexanes gradient to yield 37 mg of (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:9]=[CH:8]2
Reactant: Ic1ccccc1
Reactant: COc1cccc2cc[nH]c12
Product: COc1cccc2ccn(-c3ccccc3)c12

Procedure:
Prepared by Procedure C and Scheme O using 1H-indol-7-yl methyl ether and iodobenzene: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([C:16]([CH3:36])([CH3:35])[C@@H:17]([O:27][Si](C(C)(C)C)(C)C)[CH2:18][CH2:19]2)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].[CH:38]1C=CC=CC=1.Cl>C(O)C>[CH2:1]([O:2][C:3](=[O:37])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C:11]([C:12]3[CH2:13][CH2:14][C@@H:15]4[C@:20]([C:22]=3[CH2:23][CH2:24]2)([CH3:21])[CH2:19][CH2:18][C@H:17]([OH:27])[C:16]4([CH3:35])[CH3:36])=[CH:10][CH2:9]1)[CH3:7])[CH3:38]
Reactant: c1ccccc1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethylchola-5,7-dien-24-oic acid methyl ester (4.0 g) is suspended in a mixture of 60 ml of 96% ethanol, 10.1 ml of benzene and 10.1 ml of concentrated hydrogen chloride acid and refluxed for 3.5 hours. After aqueous work-up and column chromatography followed by crystallization from ethanol the title compound (1.37 g) is isolated. Melting point: 122-124° C. 1H-NMR (CDCl3, 300 MHz): δ=5.35 (1H, s); 4.13 (2H, q); 3.25 (1H, m). 1.25 (3H, t). MS: Calculated: 428.7. Found 428.3.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:12]2[CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:11]=2[NH:10][N:9]=1)=[O:7])C>CO>[CH3:16][C:15]1([CH3:17])[C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=2[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1n[nH]c2c1CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCc2c(C(=O)O)n[nH]c21
Yield: 43.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 15.1 mmol) was added to a stirring, room temperature solution of 2 (0.6289 g, 3.02 mmol) in MeOH (7.6 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by TLC (2.5 h). The reaction was concentrated, redissolved in EtOAc and H2O, and extracted with EtOAc. 10% aq. HCl was added dropwise until the pH=4, then the organic was removed, and the aqueous layer was extracted with EtOAc again. The combined organics were dried with Na2SO4, filtered, and concentrated. A small amount of CH2Cl2 and hexanes were added to the colored solid product, and the colored impurity was pipetted off. The remaining solid was dried to obtain 0.2371 g (43.6%) of 3 as an off-white solid. Note: The precipitation method used below appears to be the preferred protocol. 1H (CD3OD, 400 MHz): δ 2.75 (2H, t, J=6.8 Hz), 2.29 (2H, t, J=6.8 Hz), 1.29 (6H, s) ppm. 13C (CD3OD, 100 MHz): δ 166.15, 162.23, 130.46, 126.93, 47.10, 38.22, 26.62, 21.52 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 26.62; CH2 carbons: 47.10, 21.52 ppm: LCMS: 181.4 (M+1); 163.6 ((M+1)-18). HPLC: 7.538 min.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.C1COCC1.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylate (137.7 mg, 0.28 mmol, 1.00 equiv) in methanol/THF (1:1) (10 mL), and sodium hydroxide (56 mg, 1.40 mmol, 5.00 equiv) in water (3 mL) were placed in a 50-mL round bottom flask and stirred for 2 h at 40° C. in an oil bath. The mixture was concentrated by vacuum and filtered. The resulting solution was concentrated under vacuum, and the resulting solid washed with DCM/MeOH (5:1) resulting in 45 mg (33%) of 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([OH:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-chlorophenyl)-3-phenyl-2-butanone (Step D, 13 g, 50 mmol) in methanol (100 mL) at 0° C. was added sodium borohydride (3.8 g, 100 mmol). After stirring at 0° C. for 30 min, the reaction was quenched by adding 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×200 mL) The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel eluted with 10% ethyl acetate in hexane to afford the pure faster eluting isomer and a mixture containing both the faster eluting isomer and the slower eluting isomer. Faster eluting isomer: 1H NMR (500 MHz, CD3OD): δ 7.25-7.00 (m, 9H), 4.00 (m, 1H), 3.15 (m, 1H), 2.97 (m, 1H), 2.85 (m, 1H), 1.10 (d, 3H).