Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1Br)=[O:14].C[O-].[Na+]>CO>[CH3:11][O:12][C:13]([C:15]1([S:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(O)Cc1csc(S)n1
Reactant: COC(=O)C1CCCCC1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(Sc2nc(CC(=O)O)cs2)CCCCC1
Yield: 10.5 %

Procedure:
(2-Mercapto-1,3-thiazol-4-yl)acetic acid (3.50 g) synthesized in Reference Example 51 and 2-bromocyclohexanecarboxylic acid methyl ester (4.42 g) were dissolved in methanol (180 mL), sodium methoxide (2.38 g) was added and the mixture was heated under reflux for 22 hr. The solvent was evaporated, and diethyl ether (50 mL) and water (50 mL) were added to the residue. After stirring, the aqueous layer was obtained by partitioning and adjusted to about pH 4 with 1 mol/L hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:2 to 0:1) and the obtained solid was washed by suspending in hexane-ethyl acetate to give the title compound (663 mg).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=S)[CH2:11][N:10]=1.CO>O1CCCC1>[NH2:1][C:12]1[CH2:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(I)cc21
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC1=Nc2ccc(I)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 ml of 25% aqueous ammonia solution were added to a solution of 2.3 g of 5-(2-fluorophenyl)-7-iodo-3H-1,4-benzodiazepine-2(1H)-thione (A. Walser, T. Flynn, C. Mason, H. Crowley, C. Maresco, B. Yaremko & M. O'Donell, J.Med.Chem., 1991, 34, 1209) in 120 ml of tetrahydrofuran. After the addition of 5 ml of methanol the solution was stirred at room temperature for 24 h. and then evaporated in a vacuum. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The aqueous phase was extracted a further three times with chloroform. The chloroform extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethyl acetate. There were obtained 2.73 g of 2-amino -7-iodo-5-(2-fluorophenyl)-3H-1,4-benzodiazepine of m.p. 219-221° C.
Reaction SMILES: C([C@@H]1[O:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)(O)[C@@:7]([CH2:20][CH3:21])([CH3:19])[O:6]1)(C)(C)C.[OH2:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH2:34]>>[OH:6][C@:7]([CH3:19])([CH2:20][CH3:21])[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])(=[O:34])=[O:22])=[CH:13][CH:12]=1)=[O:9]
Reactant: O
Reactant: CC[C@]1(C)O[C@H](C(C)(C)C)OC1(O)c1ccc(SC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC[C@@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of the dioxolanol from Step 3 (46.2 g) in water (50 mL) with p-toluenesulfonic acid mono hydrate (1.3 g) was refluxed for 1 hour. The reaction was allowed to cool to r.t. and extract twice with EtOAc (200+150 mL). To this solution was added t-BuOH (175 mL) and Aliquat® 336. This solution was cooled to 10° C. and then a solution of OXONE® (130 g) in water (800 mL) was added over 30 min. The resulting mixture was stirred at r.t. for 20 h. The reaction mixture was neutralized by carefull and portionwise addition of aqueous saturated NaHCO3 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a yellow syrup. 1H NMR(CD3COCD3): δ0.90 (3H, t), 1.49 (3H, s), 1.81 (1 H, m), 1.95 (1H, s, OH), 1.99 (1H, m), 3.17 (3H, s), 8.02 (2H, d), 8.32 (2H, d).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15]([C:18](O)=[O:19])[S:16][CH:17]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:18]([C:15]1[S:16][CH:17]=[C:13]([Br:12])[CH:14]=1)=[O:19])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc(Br)cs1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc(Br)cs1

Procedure:
Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 4-bromothiophene-2-carboxylic acid. The residue from evaporation of the reaction mixture was partitioned between aqueous hydrochloric acid and chloroform. The aqueous layer was then basified with aqueous sodium hydroxide and extracted with chloroform. The organic extracts were dried (MgSO4), filtered, and evaporated and resulting solid was recrystallised from ethyl acetate/hexane to give the title compound as a colourless solid; MS (ES+) 315, 317 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:6][NH:7][C:8](=[NH:16])[CH:9](OCC)OCC.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:21][O:20][C:19]1[CH:18]=[C:17]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]([NH2:16])=[CH:9]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2cnc(N)cc2cc1OC
Reaction time: 8 h

Procedure:
To N-(3,4-dimethoxybenzyl)-2,2-diethoxyacetimidamide (541 mg, 1.825 mmol) was added sulfuric acid (0.95 mL, 1.825 mmol) was added. After cooling, the reaction was allowed to stand at ambient temperature overnight. It was added dropwise to ice, then the resulting solution was neutralized with conc. NaOH, and the aqueous phase was twice extracted with ethyl acetate. The combined ethyl acetate fractions were dried over magnesium sulfate. The drying agent was filtered off and the solvent evaporated. The residue was purified by column chromatography in 5% methanol/ethyl acetate, collecting the main component. Yield 105.7 mg brown solid (28%).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:38])[CH2:18][CH:19]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[CH:27][C:26]=1[O:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:6])([CH3:5])[CH3:4].CC(C)=O.C(OCC)(=O)C>C(O)C.CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:38])[CH2:18][CH:19]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]([OH:35])[CH2:32][CH2:33][CH3:34])=[CH:27][C:26]=1[O:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C(=O)CCC)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(C(O)CCC)cc1OC
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
70 mg (1.85 mmol) of sodium borohydride were added to a solution of 207 mg (0.418 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-[4-(1-oxobutyl)-2-methoxyphenyl]octanamide (prepared as described in Example 99) in 5 ml of ethanol, and the resulting mixture was stirred for 3.5 hours. At the end of this time, the mixture was ice-cooled, acetone was added to the reaction mixture to decompose any excess of the reagent, and the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography through 15 g of silica gel using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 20:0 to 20:1 by volume as the eluent, to give 203 mg (yield 98%) of the title compound as crystals, melting at 153-155° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[NH:31][C:32](=[O:36])[O:33][CH2:34][CH3:35])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[H-].[Na+].Br[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O.[Cl-].[Na+].O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:42])([F:41])[F:43])[CH:39]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[CH2:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)Nc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reactant: CCOC(=O)CCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN(C(=O)OCC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
Ethyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-carbamate (140 mg) is dissolved in N,N-dimethylformamide (1 ml), and thereto is added sodium hydride (63%) (12 mg) under ice-cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl 5-bromo-pentanoate (68 μl), and the mixture is stirred at 0° C. to room temperature overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoate (137 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1)=[O:5])C.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7][CH:6]([C:4](=[O:5])[NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]1=[O:12]
Reactant: CCOC(=O)C1Sc2ccccc2N(C)C1=O
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2nccs2)Sc2ccccc21
Yield: 15.5 %

Procedure:
A mixture of 2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one (6.22 g), 2-aminothiazole (7.43 g), and xylene (31 ml) was refluxed for 6 hours. After being cooled, the mixture was washed with 10% hydrochloric acid, water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from diethyl ether and collected by filtration. The crude crystals were purified by recrystallization from acetonitrile to yield 1.17 g of 4-methyl-2-(2-thiazolylcarbamoyl)-2H-1,4-benzothiazin-3(4H)one.
Reaction SMILES: [C:1]1([O-:12])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]([Cl:10])[C:2]=1[Cl:11].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na+].[Br-]>>[CH2:15]([O:12][C:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]([Cl:10])[C:2]=1[Cl:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [O-]c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CCCCCCBr
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCOc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
170 g (0.6 mol) of sodium pentachlorophenate and 350 ml of absolute alcohol were placed in a liter conical flask. The reactants were stirred under reflux until dissolution was complete. The condenser was removed and 97 g (83 ml:0.6 mol) of 1-bromohexane were added. The mixture was then left refluxing for about 12 hours with the stirrer on maximum speed. Solid (NaBr) was gradually deposited and on allowing the flask to stand and cool three layers were formed: a lower solid layer, an oily middle layer (the product), and an upper layer of alcohol. The flask contents were next remixed and transfered as completely as possible to a liter round bottomed flask. The alcohol was removed on a rotovap (60° C. and 100 mm), and then the flask was cooled to room temperature. 500 ml of light petrol (40/60) were added, the flask was stoppered, and then shaken vigorously for a few seconds. The pressure was next cautiously released, and the process was repeated until all the solid was in free suspension. The mixture was then rapidly filtered at the pump, then the dark brown liquid was transfered to a column of alumina (about 8"×1"). It was found that a few yellow bands moved quickly down the column. These were collected in the same receiver as the bulk of the sample--the dark colouration will collect on the top 1" of the column. A small amount of petrol was then added to wash through the column.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-thienyl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 215 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a reaction and purification procedure similar to those described in Example (59b), 1.39 g of N-[1-(3,5-difluorophenyl)ethyl]-N-[(4-ethoxyphenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 1.84 g of nickel chloride hexahydrate and 537 mg of sodium borohydride were reacted, to obtain 316 mg of isomer A and 531 mg of isomer B of the title compound as yellow oils, respectively.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:39]=[N:40][C:41]([NH2:44])=[N:42][CH:43]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]>CN1C(=O)CCC1>[CH2:13]([N:17]1[C:25]([N:26]2[CH2:31][CH2:30][N:29]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:28][CH2:27]2)=[N:24][C:23]2[C:18]1=[N:19][C:20]([C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[N:40][CH:39]=1)=[N:21][C:22]=2[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)Cn1c(N2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 1 h
Yield: 51 %

Procedure:
Triethylamine (143 μl) and mesyl chloride (50 μl, 0.63 mmol) were added to 5-(9-isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (2 ml of solution of 100 mg of this compound in 1 ml of NMP) and the resulting mixture was stirred for 1 hour. Mesyl chloride (50 μl, 0.63 mmol) was further added, the resulting mixture was stirred for 1 hour, then the reaction mixture was partitioned with ethyl acetate and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (135 mg, 51%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)=[C:4]([CH3:17])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:26]>>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([Cl:26])[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)cc(C)c1Oc1cc[n+]([O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(Br)cc(C)c1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 73 %

Procedure:
A suspension of 4-(4-Bromo-2,6-dimethyl-phenoxy)-pyridine 1-oxide (14, 10 g, 34 mmol, 1 equiv) and Na2CO3 (3.6 g, 34 mmol, 1 equiv) in POCl3 (100 mL) was heated to 105° C. for 30 h. The reaction was cooled to RT and the POCl3 was removed by rotary evaporation. The residue was dissolved in EtOAc and partioned into a chilled biphasic solution of EtOAc and 1 N NaOH. The aqueous layer was treated with NaOH (s) until the pH >1. The aqueous layer was extracted with EtOAc (3×), and the combined organics were washed with brine, dried (MgSO4) and concentrated. Recrystallization (EtOH) provided the desired material as off-white crystals (73%). 1H NMR (300 MHz, CDCl3) δ8.21 (d, J=6.2 Hz, 1H), 7.28 (s, 2H), 6.66 (m, 2H), 2.10 (s, 6H). 13C NMR (100 MHz, CDCl3) δ165.6, 153.5, 151.3, 149.0, 133.3, 132.5, 119.6, 110.7, 110.2, 16.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O[N:29]1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[C:18]([CH3:23])([CH3:22])[C:19]([NH2:29])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C(N)=O)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.5 %

Procedure:
To a stirred mixture of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanoic acid (230 mg; 0.68 mmol), ammonium chloride (180 mg, 3.4 mmol), 1-hydroxy-7-azabenzotriazole (92 mg, 0.68 mmol), anhydrous acetonitrile (5 mL), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (325 mg, 1.7 mml) was added diisopropylethylamine (0.47 mL, 2.7 mmol). The mixture was stirred under nitrogen at rt for 22 hr before concentrated in vacuo. The residue was mixed with saturated aqueous sodium bicarbonate solution (15 mL) and extracted with dichloromethane (2×10 mL). The combined dichloromethane extracts were dried (Na2SO4). Flash chromatography (SiO2 Column, 10-100% ethyl acetate in hexanes) gave 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanamide (169 mg, 0.50 mmol, 74% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 72.9 %

Procedure:
Following general procedure D, methyl 2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate (0.058 g, 0.13 mmol) was reacted with lithium hydroxide (0.026 g, 0.64 mmol) to afford the title compound (0.042 g, 75%) as a yellow-brown solid. MW=442.92. 1H NMR (DMSO-d6, 300 MHz) δ 12.29 (s, 1H), 8.32-8.24 (m, 2H), 7.71-7.53 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.53 (s, 2H), 3.80-3.70 (m, 2H), 3.52 (s, 2H), 3.21 (t, J=6.0 Hz, 2H), 2.42-2.31 (m, 2H); APCI MS m/z 443 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[OH:35]>>[OH:35][CH:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[NH:29][C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1)=[O:11])=[O:21]
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Reactant: NC1CCCC1O
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC1CCCC1O

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and 2-aminocyclopentanol (15 mg, 140 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (24 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)ccc1Sc1ccccc1
Solvent: c1ccccc1
Product: Fc1ccc(Sc2ccccc2)c(CCl)c1
Reaction time: 0.5 h

Procedure:
129 g of 3-fluoro-6-(phenylthio)-benzyl alcohol are dissolved in 385 ml of benzene and heated under reflux. 73 ml of thionyl chloride are added thereto and the resulting mixture is boiled for a further 30 minutes. The mixture is evaporated under reduced pressure. There is obtained 3-fluoro-6-(phenylthio)-benzyl chloride as a red-brown oil.
Reaction SMILES: C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)N(C3C=CC=CC=3)C2=CN=1)=O)C.[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:58])=[C:36]2[C:42](Br)=[C:41]([C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)[N:40]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1[C:35]([OH:58])=[C:36]2[CH:42]=[C:41]([C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)[N:40]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[C:37]2=[CH:38][N:39]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(F)cc1)n2-c1ccc(F)cc1
Agent: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Product: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of 2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 3-bromo-1,2-bis-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 395 (M+H+).