Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)CO>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:2][CH:3]([CH3:12])[CH3:4])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Solvent: CC(C)CO
Product: CC(C)COC(=O)Cc1ccc(-c2ccccc2)c(F)c1

Procedure:
2-methylpropyl 2-(2-fluorobiphenyl-4-yl)acetate (24) was synthesized from 2-(2-fluorobiphenyl-4-yl)acetic acid and 2-methyl propanol according to a similar procedure to step 1 of Example 15. The 1H NMR spectrum of this substance is shown below.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH:14]([C:16]([OH:18])=[O:17])[CH3:15])[C:4]1=[O:19].[CH2:20]([CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[ClH:1].[C:16]([CH:14]([N:5]1[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][CH2:9][CH:3]([NH:2][CH:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:4]1=[O:19])[CH3:15])([OH:18])=[O:17]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C(=O)O)N1C(=O)C(N)CCc2ccccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2N(C(C)C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-amino-1-(1-carboxyethyl)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride (3 g) and ethyl benzylpyruvate (6.5 g) in acetic acid (30 ml) and methanol (30 ml) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.8 g) in methanol (10 ml) was added over 4 hours. The reaction mixture was stirred at room temperature for 24 hours. Concentrated hydrochloric acid (2 ml) was added and the mixture was stirred for 1 hour. The solvents were removed at reduced pressure and the residue was partitioned between water (50 ml) and ether (30 ml). The pH was adjusted to 9.4, the ether layer was separated and discarded. The aqueous solution was adjusted to pH 4.3 and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate solutions were dried over magnesium sulfate and the solvent removed under reduced pressure. Hydrogen chloride was bubbled into a solution of the crude product in methylene chloride (10 ml) for 2 minutes. The solution was evaporated to give 1-(1-carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one hydrochloride, as a mixture of diastereomers, m.p. 87°-94°.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[CH:19]([C:21](=[O:24])[CH2:22][CH3:23])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:1][C:2]1[N:10]([CH:19]([C:21](=[O:24])[CH2:22][CH3:23])[CH3:20])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CCC(=O)C(C)Br
Reactant: Cc1[nH]c2ncccc2c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 25 °C
Yield: 7 %

Procedure:
The solution of tert-butyl 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.0 g, 4.31 mmol), 2-bromopentan-3-one (1.1 g, 6.46 mmol), Cs2CO3 (2.8 g, 8.61 mmol), KI (142.9 mg, 0.86 mmol) in CH3CN (4 ml) were stirred at 70° C. for 2 h. After the reaction completed, the solution was cooled to r.t. and filtered off. The filtration was evaporated under vacuum. The residue was purified by flash column (Eluent: PE:EtOAc=5:1) to get tert-butyl 2-methyl-1-(3-oxopentan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white oil. (100 mg yield 7%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH2:15])[CH3:14].Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:15][CH2:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
t-butoxycarbonyl- glycine (3 g), ethylamine.HCl (1.39 g), TEA (1.72 g), Hobt (2.3 g) and dry DMF (100 ml) were combined and DCC (3.5 g) was added. The mixture was stirred for three days at room temperature under nitrogen, then filtered and evaporated to dryness. 6 g of material was recovered. This material was subjected to column chromatography eluting with a gradient of ethyl acetate to ethyl acetate/methanol (1:1) providing 4.01 g of (CH3)3COC(O)NHCH2C(O)NHCH2CH3.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10](=[O:12])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.CCCCCC>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([OH:12])[CH:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of 4,4-diphenyl-2-cyclopenten-1-one (0.30 g) in toluene (3 ml) was added a 1M solution of diisobutylaluminum hydride in n-hexane (2.0 ml) at -5° C. to 4° C. After being stirred for 20 minutes, ethyl acetate (3 ml) and 10% hydrochloric acid (2 ml) was added to the solution successively, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with methylene chloride as an eluent to give 4,4-diphenyl-2-cyclopenten-1-ol (0.29 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.[OH-].[NH4+:17]>>[C:11]([C:3]1[C:2](=[O:1])[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=1)(=[O:13])[NH2:17]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnc2n(c1=O)CCC2
Yield: 96.6 %

Procedure:
10.4 g of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 30 ml of 30% by weight of ammonium hydroxide solution. The precipitated crystals are filtered after 2 hours. 8.7 g of 3-carbamoyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine are obtained with a yield of 96.6%, which melts at 293° C. after recrystallization from dimethyl formamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[C:16](OCC)(OCC)(OCC)[CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:16]([CH2:17][CH3:18])=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(OC)nc3cc(Cl)ccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 5.1 g. (0.022 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline, the product of Preparation C(d), and 60 ml. of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature (~20° C.), and the precipitate which formed was subsequently collected by means of suction filtration and washed with diethyl ether to ultimately afford 4.3 g. (75%) of pure 7-chloro-1-ethyl-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 221°-223° C.
Reaction SMILES: C(O)C.[NH2:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][CH:27]=1>[C].[Pd].C(O)(=O)C>[CH2:38]([O:37][C:35]([CH:34]([NH:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1)[CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:30]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C(=O)CCc1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccc(C)cc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
A mixture of 50 ml of ethanol, 1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 0.4 g of acetic acid, 3.6 g of ethyl 4-(p-methylphenyl)-2-oxobutyrate and 5 g of molecular sieve 4A is stirred at room temperature for 1 hour, and the mixture is subjected to catalytic reduction over 0.5 g of 5% palladium carbon, at ordinary temperature and at atmospheric pressure. After 7 hours, the catalyst is filtered off and the mixture is concentrated. The residue is treated with oxalic acid in a manner similar to that described in Example 1. The resulting oil is purified by silica gel column chromatography to give 0.3 g of tert-butyl 3(R)-[1-ethoxycarbonyl-3-(p-tolyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless oil. This product is a mixture of two diastereomers (about 1:1).
Reaction SMILES: C[O-].[Na+].Cl.[N:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][CH:6]=1.[SH:13][CH2:14][CH2:15][OH:16]>C(O)C>[OH:16][CH2:15][CH2:14][S:13][CH2:11][C:8]1[CH:9]=[CH:10][N:5]=[CH:6][CH:7]=1
Reactant: OCCS
Reactant: ClCc1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: OCCSCc1ccncc1
Temperature: 25 °C
Reaction time: 21.5 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (170.1 g., 3.15 moles, 2.1 equiv.) was dissolved in 2.7 1. of absolute ethanol, and the stirred solution cooled in an ice bath. Solid 4-picolyl chloride hydrochloride (97%, 253.6 g., 1.5 moles, 1 equiv.) was added portionwise over approximately 15 minutes. A solution of 2-mercaptoethanol (128.9 g., 1.65 moles), dissolved in 300 ml. of ethanol, was then added dropwise over approximately 30 minutes. The reaction was allowed to warm to room temperature and stirred for 21.5 hours. Diatomaceous earth was added to the reaction mixture, which after brief stirring, was filtered. The filter cake was repulped 2× 1500 ml. of absolute ethanol, the filtrates were combined with the original filtrate, and the combined ethanol solution evaporated to a solid-containing oil (approximately 290 g.). The oil was dissolved in 1500 ml. of hot chloroform, treated with activated carbon, filtered, reconcentrated to oil (274 g.) and chromatographed on 1.5 kg. of silcia gel in a 10 cm. diameter column using chloroform as eluant. Fractions of approximately 3.5 1. were taken. Fractions 3 to 18 were combined, concentrated to oil, the oil taken up in approximately 1 1. of ethyl acetate and evaporated to yield relatively pure 4-(2-hydroxyethylthiomethyl)pyridine [195.7 g., ir (film): 3.17, 3.51, 3.58, 6.27, 9.45 and 12.27μ; pnmr/CDCl3 /TMS/delta: 8.63-8.42 (m, 2H), 7.38-7.18 (m, 2H), 3.73 (t, 2H), 3.72 (s, 2H), 2.98 (s, broad, 1H) and 2.63 (t, 2H) ppm]. On standing, product prepared by this procedure slowly crystallized (m.p. 47°-48° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.[OH-:15].[Na+]>C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:15][CH2:13][CH:12]([OH:14])[CH2:11][O:10][CH2:13][CH:12]([OH:14])[CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(OCC(O)COCC(O)COc2ccc(N)cc2)cc1

Procedure:
PEG (10 g) is treated at 50° with aliquots (20 ml) of 10% aqueous glycidyl p-nitrophenyl ether and with portions (10 ml) of 10% aqueous sodium hydoxide. After 36 hours the solution is neutralized with 2 N acetic acid and evaporated. The PEG ether is extracted from the residue with benzene and precipitated by the addition of excess petroleum ether (bp 30-40).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[ClH:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[C:17]([Cl:22])=[O:19])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Product: Cl
Product: O=C(Cl)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1

Procedure:
200 mg (0.78 mmol) of trans-2-[6-(4-fluoro-phenyl)-pyridin-3-yl]-cyclopropanecarboxylic acid were dissolved in 5 ml of thionyl chloride and heated under reflux for 3 h. The mixture was evaporated to dryness. The residual oil was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)co1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)co1
Reaction time: 1 h
Yield: 58.3 %

Procedure:
tert-Butyl 4-((2-isopropyloxazol-4-yl)methyl)piperazine-1-carboxylate (0.400 g, 1.29 mmol, 1.1 eq) was dissolved in DCM (5 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (5 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)oxazole (supposedly 0.270 g, 1.29 mmol, 1 eq) was suspended in iPrOH (2.5 mL) and DIPEA (1.0 mL). To this solution, the 5-bromo-4-chloro-3-nitropyridin-2-amine (0.300 g, 1.17 mmol, 0.91 eq) was added, and the mixture heated and stirred for 17 h at 60° C. The mixture was filtered, washed with iPrOH (3×3 mL), cold H2O (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow solid (0.290 g, 53%); 1H-NMR (500 MHz, DMSO-d6): δ 1.26 (d, J=7.0 Hz, 6H, iPr—CH3), 2.52-2.64 (br s, 4H, piperazine N(CH2)2), 2.98-3.12 (m, 5H, piperazine N(CH2)2 and iPr—CH), 3.40 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.84 (s, 1H, oxazole 5-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.46 min—425/427 [(M+H)+, Br isotopic pattern, 100%].
Reaction SMILES: Br[C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C(OC)=CC=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:2]2[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: COc1cccc(N)c1Br
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: COc1cccc2nc(S)sc12
Product: COc1cccc2nc(Cl)sc12
Temperature: 120 °C

Procedure:
The title compound was prepared from 2-bromo-3-methoxyaniline via 2-mercapto-7-methoxy-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 120° C. for 10 h.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][CH:35]4[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN1CCC(CN)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCN(C)C3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-methylpyrrolidin-3-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.97 (m, 1H) 1.98-2.29 (m, 1H) 2.40-2.47 (m, 3H) 2.54-2.65 (m, 1H) 2.73-2.91 (m, 4H) 2.97-3.25 (m, 1H) 3.40 (dt, J=18.51, 6.28 Hz, 2H) 3.50-3.78 (m, 2H) 7.67 (d, J=7.33 Hz, 1H) 7.70-7.89 (m, 2H) 8.12-8.32 (m, 1H) 8.33-8.74 (m, 2H) 8.77-8.98 (m, 2H) 9.66-9.94 (m, 1H) 12.62-13.68 (m, 1H). MS m/z [M+H]+ 417.2.
Reaction SMILES: O=[O+][O-].[O:4]=O.[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=C(C)C)[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CSC>ClCCl>[CH2:6]([C:13]1[O:19][C@@H:18]2[C@@H:15]([C:16](=[O:24])[N:17]2[CH:20]=[O:4])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=O
Reactant: CC(C)=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: O=CN1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
An ozone-oxygen mixture was passed through a solution, cooled to -70° C., of 2.56 g (10 millimols) of (1S,5R)-3-benzyl-6-(2-methylprop-1-enyl)-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one (R. J. Stoodley et al., J. C. S. Perkin I 1974, 181) in 75 ml of anhydrous dichloromethane, until a blue coloration was obtained. Thereafter, flushing with nitrogen was carried out for 10 minutes, and 5.9 ml (80 millimols) of dimethyl sulphide were then added at -70° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature, and then evaporated down in vacuo. The residue was dissolved in dichloromethane, and the solution was washed with saturated NaHCO3 solution and water, and dried over MgSO4. After the solvent had been removed in vacuo, the residue was triturated with ether. 1.2 g (52%) of (1S,5R)-3-benzyl-6-formyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one were obtained as colorless crystals, melting point 90°-92° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=C)[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:37].[Na+].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:37])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)c(-c1ccc(C(C)(C)C)cc1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-vinyl-1H-indole-2-carboxylate (Example 129, 2.28 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and osmium tetroxide (2.5 weight % solution in 2-methyl-2-propanol, 1.5 mL, 0.15 mmol) was added. After ten minutes, the reaction mixture was cooled with an ice bath. Sodium periodate (2.10 g, 9.8 mmol) was added followed by a minimum volume of water to dissolve the solids. The reaction was allowed to return to room temperature, and after 30 minutes, the reaction was partitioned between water and diethyl ether. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude oil was passed through a pad of silica gel with 20% ethyl acetate/hexane. The filtrate was concentrated in vacuo without heat to provide the title compound as a brown oil (1.70 g, 75%). The product had: 1H NMR (300 MHz, acetone-d6) 10.01 (s, 1 H), 8.15 (d, 1 H), 7.88 (d, 1 H), 7.75 (d, 1 H), 7.54 (d, 2 H), 7.44 (d, 2 H), 7.21-7.19 (m, 1 H), 6.81-6.79 (m, 1 H), 6.72-6.69 (m, 2 H), 5.92 (s, 2 H), 4.12 (q, 2 H), 3.71 (s, 3 H), 1.39 (s, 9 H), 0.78 (t, 3 H).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([C:26](=[O:29])[CH2:27][OH:28])=[CH:22][N:21]=3)[C@H:16]([CH3:30])[CH2:15]2)=[C:10]([CH3:31])[C:9]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CCO>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[N:24][C:23]([CH:26]([OH:29])[CH2:27][OH:28])=[CH:22][N:21]=3)[C@H:16]([CH3:30])[CH2:15]2)=[C:10]([CH3:31])[C:9]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(=O)CO)cn3)[C@H](C)C2)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(O)CO)cn3)[C@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
To a solution of 1-[(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)-2-hydroxy-ethanone (example 114, 110 mg, 0.25 mmol) and EtOH (20 ml) is added NaBH4 (14 mg, 0.38 mmol) at 0° C. The mixture is warmed up to room temperature and stirred for 3 h. The reaction solution is acidified with 3N HCl to pH ˜7 and the organic solvent is removed. The residue is dissolved in saturated NaHCO3 solution and extracted with DCM. The organic layer is concentrated to afford the title compound (96 mg, 91%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:15]([CH3:28])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][CH:15]1[CH2:14][CH2:13][C:12](=[O:11])[CH2:17][N:16]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: C[C@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (13.17 mL, 0.150 mol) in CH2Cl2 (250 mL) at −78° C. was added DMSO (14.23 mL, 0.201 mol) dropwise. The reaction was aged for 20 min at −78° C., then ±Benzyl trans-5-hydroxy-2-methylpiperidine-1-carboxylate (25.0 g, 0.100 mol) was added dropwise over 10 min and aged for an additional 10 min before triethylamine (41.9 mL, 0.301 mol) was added dropwise over 5 min at −78° C. The reaction was warmed to room temperature, then quenched with addition of half-saturated, aqueous NaHCO3 and additional CH2Cl2. The layers were separated, and the organics were dried with MgSO4 and concentrated. The crude material was purified by silica gel gradient chromatography (0-50% ethyl acetate in hexanes), providing ±benzyl 2-methyl-5-oxopiperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(N(C(C)C)CC)(C)C.Br[CH2:50][CH2:51][CH2:52][C:53]#[N:54]>C(#N)C>[C:53]([CH2:52][CH2:51][CH2:50][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])#[N:54]
Reactant: N#CCCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](NCCCC#N)c3ccccc3)c2=O)c1F
Yield: 93.9 %

Procedure:
Compound 1f (110 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL) and diisopropylethyl amine (52 mg, 0.4 mmol) was added, followed by the addition of 4-bromobutyronitrile (90 mg, 0.6 mmol). The reaction mixture was refluxed for 16 hours. Volatiles were evaporated and the residue was purified by flash chromatography (silica, 5% MeOH/CH2Cl2) to give compound 3a (115 mg, 94%). MS (CI) m/z 613.3 (MH+).