Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[S:24][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.O>>[CH3:23][S:20]([C:17]1[N:16]=[CH:15][C:14]2[C:19](=[C:10]3[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:24][C:11]3=[CH:12][CH:13]=2)[N:18]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)c1cc2c(ccc3cnc(S(C)(=O)=O)nc32)s1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ncc2ccc3sc(C(=O)O)cc3c2n1
Yield: 98.8 %

Procedure:
2-Methanesulfonyl-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (4.20 g, 11.52 mmol) was placed in a 500 mL Florentine and cooled in an ice-bath. Pre-mixed TFA:DCM:water (1:1:0.025, 4.5 mL) was added in one portion and the resultant solution was stirred at 0° C. for 0.75 hours and a further 0.75 hours at room temperature. The reaction mixture was concentrated under reduced pressure and azeotroped with portions of DCM (5×50 mL) and Et2O (5×50 mL). The solid obtained was triturated with Et2O, filtered and washed with Et2O (3×5mL) to give a light yellow powder (3.51 g, 99% yield). δH (d6 DMSO) 3.6-3.7(3H, s), 8.3(1H, d), 8.6(1H, d), 8.8(1H, s), 9.9-10.0(1H, s), 13.8-14.0(1H, br s)
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([NH2:46])=[O:45])[CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([C:44]([NH2:46])=[O:45])[CH2:39]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)C1CCCNC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCCC(C(N)=O)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-3-carboxylic acid amide (nipecotamide, Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H41N6O3Cl2 [(M+H)+] 651.2612, observed 651.2616.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])(=[O:3])[CH3:2].[BH4-].[Na+].[OH-].[Na+].Cl>CO.O>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a suspension of methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (193 mg, 0.41 mmol, as described in Example 2.00) in methanol (2 mL) was added at −15° C. sodium tetrahydroborate (15.4 mg, 0.41 mmol). The resulting suspension was stirred at −15° C. for 20 minutes. The reaction mixture was quenched with a 2N aqueous NaOH solution (0.408 mL, 0.82 mmol) and allowed to warm to room temperature for 1 hr. More NaOH (0.408 mL, 0.82 mmol) was added and stirring was maintained for another 15 min. HCl (0.917 mL, 1.83 mmol) was added to adjust pH to 2-3. The resulting precipitate was diluted with a about 1 mL of water, collected by filtration, washed with ethyl acetate, diethyl ether and dried to a constant weight to afford 8-(1-hydroxyethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (122 mg, 94%) as a orange solid which was used without further purification. Mass Spectrum: M+H+ 320.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]2)[CH:13]=[CH:12][C:11]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>C(O)(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3].C(O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:9](=[O:27])[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([N:16]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]3)[CH:15]=2)[N:26]=[C:34]1[C:33]1[CH:36]=[CH:37][C:30]([F:29])=[C:31]([O:38][CH3:39])[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CN(c2ccc(N)c(C(=O)NCC(=O)OC(C)(C)C)c2)CC(C)(C)CN1
Reactant: COc1cc(C=O)ccc1F
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)OC(C)(C)C)ccc1F
Reaction time: 8 h
Yield: 11.9 %

Procedure:
[2-Amino-5-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)benzoylamino]acetic acid tert-butyl ester (INTERMEDIATE V.44) (1.00 g, 2.56 mmol), 4-fluoro-3-methoxybenzaldehyde (414 mg, 2.69 mmol), ethanol (20 mL) and acetic acid (3 drops) were stirred overnight at reflux temperature. Solvent was evaporated under reduced pressure. The crude reaction mixture was purified by SCX with product eluted with 2N NH3/MeOH. Solvent was evaporated under reduced pressure and the product dissolved in toluene (10 mL) and water (10 mL). Potassium hexacyanoferrate (III) (8.43 g, 25.6 mmol) was added and the reaction mixture stirred vigorously overnight. The reaction was then quenched by the addition of methanol (300 mL), the mixture filtered through a celite pad and the cake washed with further methanol (200 mL). The filtrate was evaporated to dryness and purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (3:1, v/v) as eluent to afford [2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl ester (INTERMEDIATE VII.12) (160 mg, 0.305 mmol, 12%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([Br:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[Br:20][C:4]1[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=[C:2]2[N:1]=[C:22]([CH3:23])[O:21][C:3]=12
Reactant: COC(C)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)c(Br)c2CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: Cc1nc2cc3c(c(Br)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 90 %

Procedure:
1,1-Dimethylethyl 8-amino-6-bromo-7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.604 g) was treated with trimethyl orthoacetate (0.856 ml) and pyridinium p-toluenesulfonate (112 mg) in dry DMF (23 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/6) providing the title compound as white solid (1.553 g, 90% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.[Br:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1.ClCCl>[Br:26][CH2:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:31]
Reactant: Cc1nc(N)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-amino-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide (5.60 g, 22.0 mmol) and triethylamine (2.61 g, 26.0 mmol) in anhydrous tetrahydrofuran (250 mL) was added 4-bromobutanoyl chloride (4.99 g, 26.0 mmol) in anhydrous dichloromethane (10 mL) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate solution (2×150 mL), and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrate in vacuo to afford the title compound as a yellow oil in 92% yield (8.00 g): 1H NMR (300 MHz, CDCl3) δ 8.61 (br s, 1H), 7.32-7.22 (m, 2H), 7.05-6.94 (m, 2H), 6.14 (t, J=5.6 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H), 3.45 (t, J=6.7 Hz, 2H), 2.65 (t, J=6.7 Hz, 2H), 2.58 (s, 3H), 2.23 (quintet, J=6.7 Hz, 2H); MS (ES+) m/z 413.1 (M+1), 415.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:19])([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>>[CH3:19][C:3]([CH3:2])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:26](=[O:27])[C:25]2[CH:29]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=2[O:30][CH3:31])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(CCN)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(C)(C)C(=O)O)cc1

Procedure:
By the reaction of ethyl α,α-dimethyl-β-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride with 5-chloro-2-methoxybenzoyl chloride, there is obtained α,α-dimethyl-β-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-propionic acid; m.p. 138°-141° C., after recrystallization from ethyl acetate.
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC=CC=1>CCO>[Cl:20][C:3]1[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3ccccc3)cnc21
Temperature: 80 °C
Yield: 87.1 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (3.70 g, 9.96 mmol, see Example 6) and phenylboronic acid (1.27 g, 10.5 mmol) were placed in 2:1 toluene:EtOH (30 mL). The contents were then degassed under Ar and heated to 80° C. for 24 hours. The reaction was cooled to room temperature, diluted with DCM, and poured into water. The organic fraction was filtered, dried, and concentrated. Purification was carried out by column chromatography (1:1 to 1:2 hexane:DCM) to give 4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (3.20 g, 87.1% yield).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15]>C(O)C>[C:1]1([N:7]2[C:14]([OH:15])=[CH:13][C:12]([C:11]([F:21])([F:20])[F:10])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Yield: 87.9 %

Procedure:
20 g (184.9 mmoles) of phenylhydrazine and 4 ml of concentrated hydrochloric acid were added to a solution of 34.1 g (184.9 mmoles) of ethyl trifluoroacetoacetate dissolved in 500 ml of ethanol. The mixture was refluxed for 1 hour with heating, to give rise to a reaction. After the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the most part of the solvent contained therein. The residue was mixed with water to precipitate crystals. The crystals were collected by filtration, washed with water until the filtrate became neutral, and dried to obtain 37.1 g (yield: 87.9%) of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol as ocherous crystals.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:19]([C:10]1[N:11]([CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][C:14](=[O:15])[C:9]=1[OH:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=c1ccn(CCO)c(Cc2ccccc2)c1O

Procedure:
2.14 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one (Example 1d) are hydrogenated in 200 ml of methanol over 0.5 g of palladium on carbon (5%) under normal pressure and at a temperature of 50° C. until 2 mol of H2 per mol of starting material have been taken up. The catalyst is removed by filtration and the filtrate is concentrated by evaporation using a rotary evaporator. The residue is recrystallised from ethanol, yielding 2-benzyl-3-hydroxy-1-(2-hydroxy-ethyl)-1H-pyridin-4-one in the form of colourless crystals. M.p.: 228°-230° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[N:19]1[CH:20]=[CH:21][C:16]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccncc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 60.8 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.66 g, 12 mmol) in 40 mL of THF was treated with NaH (60 percent, 0.7 g, 17 mmol). After the addition of Isonicotinic acid ethyl ester (0.3 g, 20 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Pyridine-4-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.78 g, 7.3 mmol) as red solid in 61% yield.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]#[N:21])=[CH:17][CH:18]=3)[C:13]([CH3:22])=[C:12]2[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1.[OH-].[Li+]>CO.C1COCC1>[C:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:29])=[O:2])=[CH:9][CH:8]=1)[C:12]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[C:13]2[CH3:22])#[N:21]
Reactant: COC(=O)c1ccc(Cn2c(-c3cccnc3)c(C)c3cc(C#N)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Cyano-3-methyl-2-pyridin-3-yl-indole (Example 6) is processed according to the method described in Example 11 to give 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methyl ester. To a solution of 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methyl ester (80 mg, 0.21 mmol) in methanol (5 mL) and THF (5 mL) is added 1M aqueous lithium hydroxide (2.5 mL, 2.5 mmol) and the mixture is stirred overnight at ambient temperature. The volatiles are removed in vacuo and the residue is redissolved in DMF and purified by Xbridge RP18 with a gradient of 0.1% aqueous ammonium hydroxide in acetonitrile to give 4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3H), 5.40 (s, 2H), 6.71 (d, J=8.1 Hz, 2H), 7.47-7.55 (m, 2H), 7.66 (t, J=8.6 Hz, 3H), 7.79-7.83 (m, 1H), 8.20 (d, J=1.3 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.64 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 368.1396 [(M+H)+ Calcd for C23H18N3O2: 368.1399].
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].Cl.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:20])[S:12](=[O:19])(=[O:18])[CH2:13][C:14](=O)[C:15]=2[N:16]=1>CCO.C([O-])([O-])=O.[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH3:20])[S:12](=[O:18])(=[O:19])[CH2:13][C:14](=[N:4][O:3][CH2:1][CH3:2])[C:15]=2[N:16]=1
Reactant: CN1c2ccc(Br)nc2C(=O)CS1(=O)=O
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCON=C1CS(=O)(=O)N(C)c2ccc(Br)nc21
Reaction time: 0.33 h

Procedure:
To a suspension of EtONH2.HCl (171 mg, 2.06 mmol) in EtOH (5 ml) was added K2CO3 (288 mg, 2.06 mmol) and stirring was continued for 20 min at ambient temperature. A solution of 6-bromo-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one (500 mg, 1.72 mmol) in EtOH (5 ml) was added and stirring was continued for 12 h affording a milky suspension. Since the conversion was not complete, the same amount of EtONH2.HCl in EtOH and K2CO3 were separately mixed and added to the reaction mixture affording after 60 min full conversion. The mixture was concentrated under reduced pressure followed by addition of water and ethyl acetate then the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded 6-bromo-N-ethoxy-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-imine as a yellow solid and a single isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]=[S:27]1(=[O:37])[CH2:32][CH2:31][N:30]([CH2:33][C:34](O)=[O:35])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:34](=[O:35])[CH2:33][N:30]3[CH2:31][CH2:32][S:27](=[O:37])(=[O:26])[CH2:28][CH2:29]3)[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CN1CCS(=O)(=O)CC1
Product: CN(C(=O)Cc1ccc(F)cc1)C1CN(C(=O)CN2CCS(=O)(=O)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using (1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-acetic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 556.1 [M]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[C:19]([Li])(C)(C)C.IC>>[CH3:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: CI
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
To a solution of tert-butyl 4-(trifluoromethyl)phenylcarbamate (13.2 g, 50.5 mmol) at −78° C. was added tert-butyllithium (1.7 in pentane, 62.4 mL, 106 mmol). The reaction was allowed to gradually warm to −20° C. in the ice bath (ca. 1 h). The reaction was recooled to −78° C. and treated with iodomethane (3.79 mL, 61 mmol). The reaction was allowed to gradually warm to 0° C. and held there for 15 min. The reaction was quenched by addition of saturated ammonium chloride. The mixture was poured onto diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. The solid was triturated with pentane and filtered to collect a first crop (10.4 g, 75%). The mother liquor gave a second crop of solid (2.15 g, 15%) which was again collected by filtration. 1H-NMR (CDCl3, 500 MHz) δ 8.06 (d, J=8.2 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.38 (s, 1H), 6.40 (bs, 1H), 2.28 (s, 3H), 1.53 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 152.5, 139.8, 127.2 (q, J=3.8 Hz), 126.2, 125.0 (q, J=33 Hz), 124.4 (q, J=272 Hz), 124.2 (q, J=3.8 Hz), 119.5, 81.3, 28.4, 17.7. Mass spec.: 298.00 (MNa)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7](C(O)=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)=O>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc(F)ccc2c1O
Agent: O=C=O
Product: Oc1ccnc2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 180.8 %

Procedure:
7-Fluoro-4-hydroxy-3-quinolinecarboxylic acid (25 g) was placed in a round bottom flask and heated to 330-350° C. at which time carbon dioxide liberation commenced and the material began to liquefy. After about 2 minutes an additional 25 g of 7-fluoro-4-hydroxy-3-quinolinecarboxylic acid was added. The heating was continued for an additional 4 to 6 minutes at which time there was no further evolution of carbon dioxide. The solution was allowed to cool to ambient temperature. The resulting solid was isolated by filtration to provide 35.6 g of 7-fluoro-4-quinolinol as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:16].CN(C)[C:19](=O)[CH3:20].C(C(CC)(CC)C([O-])([O-])[O-])C>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[C:3]=1[N:16]=[C:19]([CH3:20])[N:9]2[CH:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: CC(=O)N(C)C
Reactant: Nc1nc(Cl)c(N)c(NC2CCOCC2)n1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)O
Product: Cc1nc2c(Cl)nc(N)nc2n1C1CCOCC1
Temperature: 160 °C
Reaction time: 72 h

Procedure:
In an alternative procedure, the reaction was carried out in parallel using 10 vials. To each vial was added 6-chloro-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,5-triamine (preparation Route A) (400 mg, 1.64 mmol), N,N-dimethyl acetamide (8 mL), glacial acetic acid (16 μL, 0.2% vol) and triethylorthoacetate (0.8 mL, 5.32 mmol) and the mixture was stirred at 160° C. After 3 days, the reaction was complete (by LC-MS) and the reaction mixture, containing desired product MS (EI) m/z 268.1 (MH)+, as well as acetylated product MS (EI) m/z 310.2 (MH)+, was cooled to room temperature. To each vial was then added 1 mL of a 1 M aqueous solution of HCl, with stirring at 100° C. After 1 h at 100° C., LC-MS analysis indicated only desired product, in a clean reaction. Upon cooling to room temperature, a white precipitate formed. Filtration under vacuum, followed by washing of the precipitate with portions of methanol provided the desired product (combined yield 2.98 g for 10 vials, 68% yield) as a white solid in pure form. 1HNMR (300 MHz, d6-DMSO) δ, ppm: 6.76 (s, 2H), 4.41 (m, 1H), 3.97 (m, 2H), 3.45 (m, 2H), 3.33 (s, 3H), 2.63 (m, 2H), 1.74 (m, 2H); MS (EI) m/z 268.1 (MH)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C)=O)[CH2:3]1.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)NC2C=NC=CN=2)C1.F[C@H]1CN[C@H](C(NC2C=NC=CN=2)=O)C1>>[OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: Nc1nccs1
Agent: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Agent: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Product: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1

Procedure:
(2S,4S)-4-Hydroxy-N-(thiazol-2-yl)pyrrolidine-2-carboxamide 88A was prepared from (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate and 2-Amino thiazole as described for 65A and 65B. LC/MS [M+H]+: 214; Ret time (Method F): 0.35 min.