Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[CH:10]=[C:11]([C:13]([O:15]CC)=O)[N:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[NH2:18][NH2:19]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]2[CH:10]=[C:11]([C:13]([NH:18][NH2:19])=[O:15])[N:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cn2c(n1)CN(C(C)=O)CC2
Reactant: NN
Product: CC(=O)N1CCn2cc(C(=O)NN)nc2C1
Reaction time: 0.33 h

Procedure:
6 g of the ester thereby obtained, in 10 ml of hydrazine, are brought to the refluxing temperature for 20 min. The excess hydrazine is evaporated off and the oil obtained purified by chromatography on a silica column (methylene chloride/methanol/ammonia solution 19:10:1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:7]1)=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O>[NH2:12][C@H:11]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH2:7][C@@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1CN(CCc2ccc(OC)c(OC)c2)CC[C@@H]1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCN2CC[C@H](N)[C@@H](C(=O)O)C2)cc1OC
Yield: 37.5 %

Procedure:
(3R,4R) and (3S,4S)-4-Amino-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (262 mg) and lithium hydroxide (166 mg) in 5 ml THF, 5 ml MeOH and 1 ml H2O were stirred for 24 h at ambient temperature. The mixture was diluted with buffer pH 7 and extracted with AcOEt. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (Isolute SPE Flash NH2, AcOEt) and precipitated (AcOEt/heptane) to give 90 mg (37%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][NH:29]3)=[N:23][C:22]=2[CH:35]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=3)=[O:9])=[N:23][C:22]=2[CH:35]=1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](=O)[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:14].[K+].Br[CH2:17][C:18](C1C=CC=CC=1)=O.Cl>O>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:17]=[C:18]([OH:14])[C:7]([CH3:6])=[N:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C1Nc2c(ccc(F)c2F)C1=O
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1nc2c(F)c(F)ccc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
41 g of the crude product of 6,7-difluoroisatin were added to 200 mL of water followed the addition of 75.3 g (6 equivalents) of potassium hydroxide while cooling with ice and stirring the mixture for 30 minutes. 42 g (1.4 equivalents) of bromoacetophenone were dropped into the resultant suspension at a temperature of 20° C. to 25° C. Following completion of dropping, the reaction mixture was stirred overnight at room temperature. The resultant was then neutralized with concentrated hydrochloric acid. The precipitated crystals were removed by filtration and washed with a small amount of water. The resulting crystals were dried, and then added to 100 mL of nitrobenzene a little at a time at 130° C. to 140° C. Following completion of addition, the reaction mixture was stirred for 1 hour at 150° C. After cooling the reaction mixture to room temperature, the precipitated crystals were washed with chloroform to obtain 26.3 g of 7,8-difluoro-3-hydroxy-2-methylquinoline.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.O>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:16]([C:3]2[C:2](=[O:1])[N:7]3[C:8]4[C:13]([N:14]=[CH:15][C:6]3=[N:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:18])=[N:36][N:35]=[N:34]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnc2cnc3ccccc3n2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cnc2cnc3ccccc3n2c1=O
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of 250 mg of 1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxylic acid and 200 mg of carbonyldiimidazole in 5 ml of dry dimethylformamide was heated over a steam bath for 15 minutes and then 100 mg of 5-aminotetrazole were added thereto. The mixture obtained was heated over a steam bath for another 30 minutes and was then poured into water and left at room temperature for 1 hour. The solid obtained was filtered off, was washed with water and ether and dried to obtain 240 mg (61% yield) of N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxamide melting above 300°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[C:17]([CH3:22])=[N:18][N:19]([CH3:21])[CH:20]=1>CO.C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:15][C:16]1[C:17]([CH3:22])=[N:18][N:19]([CH3:21])[CH:20]=1
Reactant: Cc1nn(C)cc1Nc1c([N+](=O)[O-])cnc2ccc(Br)cc12
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(C)cc1Nc1c(N)cnc2ccc(Br)cc12

Procedure:
(6-Bromo-3-nitro-quinolin-4-yl)-(1,3-dimethyl-1H-pyrazol-4-yl)-amine (Stage A.3, 3.67 g 9.73 mmol) was shacked in MeOH/THF 1:1 (120 ml) under 1.1 bar H2 in presence of Raney nickel (1.50 g) as catalyst for 5 h at rt. The RM was filtered over celite, the catalyst was washed with MeOH/DCM and the solution was evaporated to dryness to give the title compound as a red solid (HPLC tR 2.44 min (Method A); M+H=334; M−H=332 MS-ES)
Reaction SMILES: O.[BH4-].[Na+].[C:4]([O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]1[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:6])[CH3:5].C(O)(=O)C>CO>[C:4]([O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]1[CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:6])[CH3:5]
Reactant: CCOC(=O)C(=O)c1cc(Br)cn1CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(=O)C(O)c1cc(Br)cn1CCOC(C)=O
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
Methanol (100 ml) containing 2.5 ml water is cooled to -50° C. and 3.07 g of sodium borohydride (81.2 mmole) is added with stirring. After 5 minutes, ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glyoxalate (8.9 g -26.7 mmole) is dissolved in 40 ml methanol and added at a rate such that the reaction temperature does not exceed -40° C. After 1 hour at this temperature, 50% aqueous acetic acid is added until the solution is weakly acidic. The methanol is then removed in vacuo, 100 ml ethyl acetate is added to the residue, and the organic phase is washed well with saturated salt solution and then dried over sodium sulfate. The solvent is removed in vacuo and the residue is immediately crystallized, at low temperature (dry ice-acetone bath), from ether. The ethyl 1-(2-acetoxyethyl)-4-bromopyrrole-2-glycolate thus obtained (6.0 g, 67%) exhibits a m.p. of 59° C. but is unstable and is be stored in an evacuated vessel at -10° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])N=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].S1C=CC=[C:33]1C1C=CC=CC=1C(O)=O>>[CH3:33][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:23]([C:22]4[CH:26]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=4[N:27]4[N:31]=[CH:30][CH:29]=[N:28]4)=[O:24])[CH2:15]3)[CH2:10]2)[CH:8]=1
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)c1

Procedure:
The title compound was prepared in a manner analogous to Example 1 substituting Intermediate 43 for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid for 2-thiophene-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H23FN6O, 406.5; m/z found, 408.2 [M+H]+.
Reaction SMILES: [Na].[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[CH:8]=1.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[OH:2][C:3]1[CH2:4][CH:5]([C:10]([OH:12])=[O:11])[CH2:6][C:7](=[O:9])[C:8]=1[N:21]=[N:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#[N+]c1ccccc1
Reactant: O=C1C=C(O)CC(C(=O)O)C1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: O=C1CC(C(=O)O)CC(O)=C1N=Nc1ccccc1

Procedure:
13.8 g. of sodium were dissolved in 900 ml. of methanol and to this solution were added 46.8 g. of 3-hydroxy-5-keto-3-cyclohexene-carboxylic acid. The resulting mixture was stirred, maintained between -4° C. and -8° C. by means of a cooling bath and treated over a period of 30 minutes with a phenyl-diazonium chloride solution (prepared from 27.9 g. of aniline, 450 ml. of water, 72 ml. of concentrated hydrochloric acid and 21.0 g. of sodium nitrite in 90 ml. of water). The resulting mixture was stirred for an additional hour at -5° C. to -10° C. The precipitated red reaction product was removed by filtration with suction and washed with about 1000 ml. of water, whereby there was obtained 3-hydroxy-5-keto-4-phenylazo-3-cyclohexene-carboxylic acid having a melting point of 218° C.
Reaction SMILES: C[CH2:2][N:3](C(C)C)C(C)C.FC(F)(F)C([O-])=O.[F:17][C:18]([F:26])([F:25])[CH2:19][NH:20][C:21]([NH2+]C)=[O:22].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:60][C:61]1[CH:62]=[C:63]([C:68]2([C:82]([F:85])([F:84])[F:83])[O:72][N:71]=[C:70]([C:73]3[S:77][C:76]([C:78](O)=[O:79])=[C:75]([CH3:81])[CH:74]=3)[CH2:69]2)[CH:64]=[C:65]([Cl:67])[CH:66]=1>ClCCl>[F:26][C:18]([F:17])([F:25])[CH2:19][NH:20][C:21]([CH2:2][NH:3][C:78]([C:76]1[S:77][C:73]([C:70]2[CH2:69][C:68]([C:63]3[CH:62]=[C:61]([Cl:60])[CH:66]=[C:65]([Cl:67])[CH:64]=3)([C:82]([F:85])([F:84])[F:83])[O:72][N:71]=2)=[CH:74][C:75]=1[CH3:81])=[O:79])=[O:22]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[NH2+]C(=O)NCC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)NCC(=O)NCC(F)(F)F

Procedure:
DIPEA (0.246 ml) is added to a solution of (2,2,2-trifluoro-ethylcarbamoyl)-methyl-ammonium trifluoroacetate (0.170 g, Example 4, step B), PYBOP (0.270 g), and 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (0.2 g) in dichloromethane (3 ml) at 0° C. After 30 minutes at room temperature the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with a saturated aqueous solution of NaCl and a saturated aqueous solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative reversed phase HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (8.73 g) as a beige foam. MS (HPLC/MS): 562 (MH+). Retention time: 3.94 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:12])[CH:6]=[CH:5]2.BrC1C=C2C(=CC=1[Cl:24])C=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:24])[CH:8]=[N+:7]([O-:12])[CH:6]=[CH:5]2
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Reactant: Clc1cc2cnccc2cc1Br
Product: [O-][n+]1ccc2cc(Br)c(Cl)cc2c1

Procedure:
The title compound was prepared by the method, described for 6-Bromo-isoquinoline 2-oxide (4), starting with 6-Bromo-7-chloro-isoquinoline (9). Rt=1.05 min (Method C). Detected mass: 258.1/260.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])[C:5]([C:7]1([S:15]CC2C=CC(OC)=CC=2)[CH2:12][CH2:11][N:10]([O:13][CH3:14])[CH2:9][CH2:8]1)=[O:6].[OH-].[Na+]>FC(F)(F)C(O)=O.O>[OH:6][C:5]1[C:7]2([CH2:8][CH2:9][N:10]([O:13][CH3:14])[CH2:11][CH2:12]2)[S:15][C:3](=[O:2])[C:4]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33]
Reactant: COC(=O)C(C(=O)C1(SCc2ccc(OC)cc2)CCN(OC)CC1)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CON1CCC2(CC1)SC(=O)C(c1c(C)cc(C)cc1C)=C2O
Temperature: 25 °C
Yield: 48.3 %

Procedure:
470 mg 3-[1-Methoxy-4-(4-methoxy-benzylsulfanyl)-piperidin-4-yl]-3-oxo-2-(2,4,6-trimethylphenyl)-propionic acid methyl ester (from Step 6) was dissolved in 15 ml trifluoroacetic acid and heated on reflux for 18 hours. The mixture was cooled to room temperature, diluted with water, the pH adjusted to 4.2 by the addition of aqueous sodium hydroxide, then extracted with t-butylmethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent evaporated. The residue was chromatographed on silica gel with ethyl acetate/cyclohexane (1:1, then 2:1) as a solvent, to yield 156 mg 4-hydroxy-8-methoxy-3-(2,4,6-trimethyl-phenyl)-1-thia-8-aza-spiro[4.5]dec-3-en-2-one (compound P2.4) as a solid, mp 67-71° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][C@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][C@H:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(C[C@@H](C)O)CC2
Yield: 63 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. Product was isolated as an off-white foam (65 mg, 63%). MS (ESI+): 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.08 (s, 1H), 2.88 (m, 8H), 2.62 (br s, 2H), 2.53 (m, 2H), 2.27 (m, 2H), 1.66 (d, J=8.5 Hz, 1H), 1.16 (d, J=6 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].C(NC(C)C)(C)C.[F:15][C:16]([F:20])=[C:17]([F:19])[F:18]>CN(C)C=O>[F:15][C:16]([F:20])([S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:17]([F:19])[F:18]
Reactant: Sc1ccccn1
Reactant: FC(F)=C(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: FC(F)C(F)(F)Sc1ccccn1
Temperature: 50 °C
Yield: 296.6 %

Procedure:
A mixture of 42 grams of 2-pyridinethiol, 1-oxide, 150 ml of dimethylformamide and 36 grams of diisopropylamine in a stainless steel pressure vessel was pressurized with 4.95 grams of tetrafluoroethylene at -20° C. and heated to 50° C. for 6 hours with rocking. After cooling to ambient temperature, the pressure vessel was vented and the resulting reaction solution was poured into 300 ml of ice water. The aqueous reaction mixture was extracted four times, using 300 ml of diethyl ether each time. The combined diethyl ether extracts were washed three times, using 500 ml of cold water each time. After washing the diethyl ether solution once with 500 ml of saturated aqueous sodium chloride solution, the diethyl ether solution was dried over 100 grams of anhydrous sodium sulfate and evaporated under reduced pressure of 300 mm Hg to 49.6 grams of a semisolid. The semisolid was crystallized from 1-chlorobutane to yield 31 grams of 2-(1,1,2,2-tetrafluoroethylthio)pyridine, 1-oxide melting 67.5°-68.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]=12.Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Li+].[BH4-]>C1COCC1>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[CH2:7][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:10][C:2]=12
Reactant: CCOC(=O)Cl
Reactant: c1cc2nccnc2cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C=Cc2nccnc2C1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
A solution of pyrido[3,4-b]pyrazine (20.0 g, 153 mmol) in anhydrous THF (250 mL) is cooled to −25° C. A solution of ethyl chloroformate (17.5 ml, 183 mmol) in THF (46 mL) is added dropwise. The mixture is stirred 1 hr at −25° C., and then LiBH4 (2.0 M, 23 mL, 46 mmol) is added dropwise and the mixture is stirred for 1 hr. The reaction is quenched with the addition of 1N NaOH (100 mL) and extracted with Et2O (3×100 mL). The organic extractions are combined, dried and evaporated. The crude product is purified by silica gel column chromatography eluting with hexane/EtOAc (3:2) to yield the title compound. MS (+VE) m/z 206.14 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[F:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([S:29]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CCC(=O)O
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc2c2cc[nH]c12
Yield: 23.2 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 29 μL (0.21 mmol) of 3-fluoro-benzenesulfonyl chloride. After recrystallization from methanol then trituration in hot methanol, 20 mg (24%) of 8-(3-fluoro-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH:12]=O.[NH2:16]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO>[CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]#[N:16]
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Reactant: NO
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[Si](C)(C)CCOCn1ccnc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde (1.5 g, 6.6 mmol) in 5 mL of MeOH was added hydroxylamine (0.6 mL, 9.1 mmol, 50% aqueous soln) and the reaction stirred for 10 min at RT and then concentrated. The residue was dissolved in 10 mL of DCM and 5 mL of pyridine and cooled in an ice bath. To this mixture was added trifluoroacetic anhydride (4.2 g, 20 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated and then dissolved in EtOAc (50 mL) and washed with NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated to give 1.2 g (81%) of a brown oil of sufficient purity to use in the next step. 1H-NMR (CDCl3, 400 MHz): δ 7.28 (s, 2H), 5.48 (s, 2H), 3.56 (m, 2H), 0.96 (m, 2H), 0.00 (s, 9H). Mass spectrum (APCI, m/z): Calcd. for C10H17N3OSi, 224.1 (M+H), found 223.6.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N:19]1[CH:23]=[N:22][N:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:34])=[CH2:33].O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:31]=[C:32]([CH3:34])[CH3:33])=[C:3]([N:19]3[CH:23]=[N:22][N:21]=[N:20]3)[CH:4]=2)[S:9][C:10]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(-n3cnnn3)c2)nc1C
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(OC=C(C)C)c(-n3cnnn3)c2)nc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A solution was prepared by dissolving 33.1 mg of ethyl 2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate in 1.0 mL of dimethylformamide. A reaction mixture solution prepared by adding 20.7 mg of potassium carbonate and 16.2 mg of 3-bromo-2-methylpropene to the solution was heated under stirring at 100° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, followed by concentrating the organic phase to obtain 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (2) A reaction mixture solution prepared by adding 1.0 mL of 35% sulfuric acid aqueous solution to 34.1 mg of ethyl 4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate was heated under stirring at 80° C. for 4 hours. The reaction mixture solution was cooled to room temperature and then 3 mL of water and 4 mL of ethyl acetate were added under stirring, and the organic phase was concentrated and purified using a conventional method to obtain 9.9 mg of ethyl 2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:49]([OH:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:37]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:46]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:47])[C:49]([OH:52])([CH3:50])[CH3:51])([CH3:40])([CH3:38])[CH3:39]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) and DMF (500 μL) at 0-5° C. was treated with diisopropylethylamine (87 μL, 0.50 mmol), (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (64 mg, 0.28 mmol), followed by HATU (105 mg, 0.28). The reaction mixture was allowed to warm to room temperature and stir for 3 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 30% then 40% EtOAc/hexanes as eluant to afford the intermediate {(R)-1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-2-hydroxy-2-methyl-propyl}-carbamic acid tert-butyl ester as an oil (100 mg, 69%). LC/MS (Method B) 4.36 min, [M+1]+ 582.