Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:34](F)=[CH:33][C:18]([C:19]([C:21](=[CH:27][NH:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17](F)[C:16]=2[F:37])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:16]([F:37])=[CH:17][C:18]3[C:19](=[O:20])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][N:28]4[CH:29]([CH3:32])[CH2:30][O:31][C:34]=2[C:33]=34)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNC(C)CO)C(=O)c1cc(F)c(C2(NC(=O)OCc3ccccc3)CC2)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OCC2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.8 %

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 3.07 g of ethyl 2-[4-(1-benzyloxycarbonylaminocyclopropyl)-2,3,5-trifluorobenzoyl]-3-(2-hydroxy-1-methylethylamino)acrylate. To the resulting solution was added 519 mg of 60% sodium hydride with ice-cooling. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 760 mg (yield: 26.9%) of ethyl 10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[CH:16]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:31][S:28]([C:24]1[CH:23]=[C:22]([NH:21][C:17]2[N:18]=[CH:19][N:20]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[OH:8])[CH:16]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:29])=[O:30]
Reactant: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3OCc3ccccc3)ncn2)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(Nc2cc(-c3ccccc3O)ncn2)c1

Procedure:
A mixture of [6-(2-benzyloxy-phenyl)-pyrimidin-4-yl]-(3-methanesulfonyl-phenyl)-amine (7.90 g, 18.3 mmol) and trifluoroacetic acid (100 mL) was refluxed to completion of the reaction. All the volatiles were evaporated in vacuo, the residue was re-crystallized from ethanol to give 2-[6-(3-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-phenol as white powder.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:27])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=3[C:8]2=[O:24])=[CH:25][CH:26]=1
Reactant: COc1cnc(NS(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 2 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]methanesulfonamide (0.097 g, 0.256 mmol) in DMF (2 mL) was added Cs2CO3 (0.083 g, 0.256 mmol) and MeI (0.04 g, 0.28 mmol, dissolved in DMF). After stirring for 2 hours, additional MeI (0.02 g, 0.14 mmol) was added. The product mixture was concentrated. The residue was partitioned between CHCl3 and pH 7 buffer. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the title compound.
Reaction SMILES: C1COCC1.C([O:9][CH2:10][CH2:11][O:12][C@H:13]1[C@H:45]([O:46][Si:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][CH3:49])[C@@:44]2([CH3:54])[C:16](=[CH:17][CH:18]=[C:19]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:55])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:39])[CH2:25][CH2:26][CH2:27][C:28]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([CH3:30])[CH3:29])[CH2:15][C@H:14]1[O:56][Si:57]([CH2:62][CH3:63])([CH2:60][CH3:61])[CH2:58][CH3:59])(=O)C.CO.[OH-].[K+]>O.C(O)(=O)C>[OH:9][CH2:10][CH2:11][O:12][C@H:13]1[C@H:45]([O:46][Si:47]([CH2:48][CH3:49])([CH2:50][CH3:51])[CH2:52][CH3:53])[C@@:44]2([CH3:54])[C:16](=[CH:17][CH:18]=[C:19]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:55])[C@H:20]3[CH2:21][CH2:22][C@@H:23]2[C@H:24]([CH3:39])[CH2:25][CH2:26][CH2:27][C:28]([O:31][Si:32]([CH2:35][CH3:36])([CH2:33][CH3:34])[CH2:37][CH3:38])([CH3:29])[CH3:30])[CH2:15][C@H:14]1[O:56][Si:57]([CH2:58][CH3:59])([CH2:60][CH3:61])[CH2:62][CH3:63]
Reactant: CC[Si](CC)(CC)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O[Si](CC)(CC)CC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](CC)(CC)CC)[C@@H]1OCCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)O[Si](CC)(CC)CC)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](CC)(CC)CC)[C@@H]1OCCO
Temperature: 22.5 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To a THF (5 ml) solution of compound 4 (327 mg, 380 μmol) obtained in Example 2, a methanol (10 ml) solution of potassium hydroxide (72 mg, 1.29 mmol) was added, and the mixture was stirred in an argon atmosphere for 1.5 hours at 15 to 30° C. To the reaction mixture, acetic acid (150 μl) was added. Then, the resulting mixture was poured into water, extracted twice with a solvent mixture of ethyl acetate and hexane (1:1), and washed with a saturated solution of sodium carbonate and a saturated aqueous solution of sodium chloride in this order. The organic phase was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (8% ethyl acetate/hexane) to give colorless oily compound 5 (173 mg, 56%).
Reaction SMILES: [P:1]([O:27]CC=C)([O:23]CC=C)([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[C@@H:8]([OH:11])[C@H:7]([N:12]2[CH:17]=[C:16]([F:18])[N:15]=[C:14]([C:19]([NH2:21])=[O:20])[C:13]2=[O:22])[O:6]1)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O.C(N)CCC>CO.O1CCCC1.O>[CH2:7]([NH2:12])[CH2:8][CH2:9][CH3:5].[P:1]([OH:27])([OH:23])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[C@@H:8]([OH:11])[C@H:7]([N:12]2[CH:17]=[C:16]([F:18])[N:15]=[C:14]([C:19]([NH2:21])=[O:20])[C:13]2=[O:22])[O:6]1)=[O:2]
Reactant: C=CCOP(=O)(OCC=C)OC[C@H]1O[C@@H](n2cc(F)nc(C(N)=O)c2=O)[C@H](O)[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCN
Solvent: O=CO
Product: NC(=O)c1nc(F)cn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
In a mixture of 8.2 mL of methanol and 8.2 mL of tetrahydrofuran was dissolved 0.82 g of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl diallyl phosphate under a stream of nitrogen gas. After adding 0.11 g of tetrakis-triphenylphosphine palladium (0) and 0.28 g of triphenylphosphine successively, the mixture thus obtained was stirred at room temperature for 30 minutes. While cooling the reaction mixture with ice, a solution of 0.68 mL of formic acid in 1.9 mL of tetrahydrofuran and a solution of 0.25 mL of n-butylamine in 8.2 mL of tetrahydrofuran were successively added. The mixture thus obtained was stirred at 30-35° C. for one hour and then at 40-45° C. for 2 hours. The reaction mixture was diluted with 10 mL of water, and the organic solvent was removed under reduced pressure. The aqueous solution thus obtained was washed with 20 mL of chloroform, and the washings were extracted with 30 mL of water. All the aqueous layers were united, and the solvent was removed under reduced pressure. The residue thus obtained was purified by reversed phase silica gel column chromatography [eluent: water]. Thus, 0.29 g of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl dihydrogen phosphate n-butylamine salt was obtained as a yellow-colored solid product.
Reaction SMILES: BrC1C=CC(N)=CC=1.CC1(C)OC(=O)CC(=O)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[Br:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:27](=[O:32])[CH:28]=[C:29]2[OH:31]
Reactant: O=C(O)CC(=O)Nc1ccc(Br)cc1
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CS(=O)(=O)O
Agent: Nc1ccc(Br)cc1
Solvent: O
Product: O=c1cc(O)c2cc(Br)ccc2[nH]1
Temperature: 80 °C

Procedure:
According to the general method described in Synthetic Communications 2010, 40, 732, a mixture of 4-bromoaniline (30.0 g, 174 mmol) and 2,2-dimethyl-1,3-dioxan-4,6-dione (25.1 g, 174 mmol) was heated to 80° C. for 1.5 hours and cooled to ambient temperature to receive 3-((4-bromophenyl)amino)-3-oxopropanoic acid. The acetone byproduct was removed under vacuum to provide the intermediate product as a dry solid. Eaton's reagent (100 mL) was added to the solid, and the resulting mixture heated to 70° C. overnight then cooled to room temperature. The mixture was poured into water and the brown precipitate was filtered and rinsed with water. The brown precipitate was triturated with ethanol, then filtered to provide the title compound as a light brown solid.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:22]([O:29][C:30]([NH:32][CH2:33][C:34](Cl)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([NH:32][CH2:33][C:34]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C(Cl)CNC(=O)OCc1ccccc1
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)OCc1ccccc1
Yield: 61 %

Procedure:
The title compound, a white crystalline, was prepared by acylation of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine with N-benzyloxycarbonylglycine chloride in a similar way as described under Example 19. Yield: 61%
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.[NH:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][N:17]=1)[NH2:15]>CO>[N:15](=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1)[N:14]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1
Reactant: CCOC1=NCCc2ccccc21
Reactant: NNC1=NCCc2ccccc21
Solvent: CO
Product: c1ccc2c(c1)CCNC2=NN=C1NCCc2ccccc21

Procedure:
A solution of 1-ethoxy-3,4-dihydroisoquinoline (4.25 g.) and 1-hydrazino-3,4-dihydroisoquinoline (3.9 g.) in methanol (40 ml.) was stirred at room temperature overnight and then at reflux for a day. More 1-ethoxy-3,4-dihydroisoquinoline (1 g.) was added during the reflux period. The solution was stripped of methanol and the solid was recrystallized from 2-propanol, affording 1,1'-azinobis(1,2,3,4-tetrahydroisoquinoline) (II: Y=Y' =Z=Z' H) (first crop, 2.6 g., m.p. 178°-179° C.). In this example 1-hydrazino-3,4-dihydroisoquinoline hydrochloride can be used instead of 1-hydrazino-3,4-dihydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27](F)[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1.[CH2:35]([OH:37])[CH3:36].[H-].[Na+].O>CN(C)C=O>[CH3:34][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:37][CH2:35][CH3:36])[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CCO
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(S(=O)(=O)N2CC(C)(C)Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
165 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile and 30 ml ethanol were dissolved in 3 ml dimethylformamide. Then 10 mg sodium hydride were added and the reaction mixture stirred at room temperature for 4 hours. The mixture was then poured into 20 ml water and extracted five times with portions of 20 ml ethyl acetate. The combined organic extracts were dried over MgSO4 then evaporated in vacuo and the residue purified by chromatography on silica gel to obtain 40 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-benzonitrile.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:37][C:36]5[CH:39]=[CH:40][C:33]([O:32][C:31]([F:30])([F:41])[F:42])=[CH:34][CH:35]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (45 mg, 0.139 mmol, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.5 mL) in a 4-mL scintillation vial. Triethylamine (28.0 mg, 0.277 mmol) was added followed by the addition of 4-(trifluoromethoxy)benzaldehyde (34.2 mg, 0.180 mmol) as a solution in dichloromethane (0.2 mL). The resulting solution was stirred at room temperature for 15 minutes, at which point sodium triacetoxyborohydride (70.5 mg, 0.333 mmol) was added as a neat solid in one portion, and the resulting suspension was stirred at room temperature for an additional 4 hours. The suspension was loaded directly onto a 4 g silica column and eluted with ethyl acetate (flow rate=18 mL/minute) over 15 minutes to give the title compound as a colorless oil (34 mg, 53%). 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=1.2 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.41 (t, J=3.9 Hz, 1H), 4.18 (dd, J=16.4, 9.4 Hz, 1H), 4.02 (dd, J=13.7, 2.0 Hz, 1H), 3.69-3.45 (m, 3H), 2.94 (d, J=12.5 Hz, 2H), 2.81 (d, J=12.0 Hz, 1H), 2.60 (dd, J=14.8, 6.9 Hz, 1H), 2.50-2.34 (m, 2H), 2.15 (dd, J=12.8, 9.3 Hz, 1H), 1.98 (tt, J=7.9, 5.1 Hz, 1H), 1.86 (ddd, J=14.4, 10.4, 4.4 Hz, 1H), 1.02-0.79 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [α]D24.1=−0.04 (c=0.23, CH3OH).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:24]=[C:7]2[N:8]=[C:9]([C:16]3[C:17]([CH3:23])=[N:18][N:19]([CH2:21]C)[CH:20]=3)[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:6]2[N:5]=1.Cl>C(O)C>[Br:3][C:4]1[CH:24]=[C:7]2[NH:8][CH:9]([C:16]3[C:17]([CH3:23])=[N:18][N:19]([CH3:21])[CH:20]=3)[CH2:10][CH:11]([C:12]([F:13])([F:14])[F:15])[N:6]2[N:5]=1
Reactant: CCn1cc(-c2cc(C(F)(F)F)n3nc(Br)cc3n2)c(C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1C1CC(C(F)(F)F)n2nc(Br)cc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
Sodium tetrahydroborate (472 mg) was slowly added to a suspension of 2-bromo-5-(1-ethyl-3-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (Preparation 7, 1.8 g) in Ethanol (20 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was then very slowly added to ice cooled 1N HCl until a pH=2.0 was achieved to quench any remaining sodium tetrahydroborate. The solution was then concentrated under high vacuum to remove the majority of ethanol. Saturated sodium bicarbonate aqueous solution was then slowly added to the acidic solution until a neutral pH (7.0) was achieved and a white precipitate forms. The precipitate was filtered off and washed with water (200 mL) and ether (20 mL). The white precipitate was collected and dried in vacuo to afford the title compound as a white powder (1.36 g, 74.7%). 1HNMR (400 MHz, DMSO-d6) δ: 2.00, (m, 1H), 2.09, (s, 3H), 2.30, (m, 1H), 3.67, (s, 3H), 4.34, (m, 1H), 5.15, (m, 1H), 5.31, (s, 1H), 6.69, (s, 1H), 7.63, (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([F:10])=[C:8]([O:11][CH3:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[N:6]=1)=[O:4].[OH-].[Li+].O.Cl>O1CCOCC1>[F:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:8]=1[O:11][CH3:12]
Reactant: COC(=O)c1nn(-c2ccccc2F)c(OC)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(F)c(C(=O)O)nn1-c1ccccc1F
Temperature: 56 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
70 mg (0.26 mmol) of 4-fluoro-1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester were dissolved in 1.3 ml of dioxane and 1.305 ml of a 1 M aqueous solution of lithium hydroxide were added. The mixture was stirred at 56° C. for 30 min, then water and 2 N hydrochloric acid were added and the mixture extracted with diethyl ether. The organic phase was evaporated to give 67 mg (33%) of the title compound.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([CH:20]=O)[NH:17]2)=[CH:13][CH:12]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:22]1([CH2:20][C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([O:10][C:2]2[S:1][C:9]4[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH:19]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=Cc1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1cnc2nc(Oc3ccc4cc(CN5CCCCC5)[nH]c4c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a suspension of 6-(thiazolo[4,5-b]pyridin-2-yloxy)-1H-indole-2-carbaldehyde (76 mg, 0.26 mmol) in DCM (3 mL) was added piperidine (0.05 mL, 43 mg, 0.51 mmol), Na(OAc)3BH (65 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 12 h). The reaction mixture was partitioned between saturated NaHCO3 (10 ml) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (12 mg, 13%). MS (ESI): mass calcd. for C20H20N4OS, 364.1; m/z found, 365.1 [M+H]+. 1H NMR (500 MHz, CDCl3/CD3OD, 10/1): 8.51 (d, J=4.8, 1H), 7.97 (d, J=7.9, 1H), 7.54 (d, J=8.5, 1H), 7.40 (s, 1H), 7.18 (dd, J=7.9, 4.9, 1H), 7.02 (d, J=8.5, 1H), 6.36 (s, 1H), 3.63 (s, 2H), 2.53-2.47 (m, 2H), 2.47-2.36 (m, 2H), 1.76-1.44 (m, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1CCN>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[S:12]
Reactant: NCCc1ccccc1Cl
Reactant: S=C(Nc1nc2ccccc2s1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1Cl)Nc1nc2ccccc2s1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of 1-[(2-benzothiazolyl)-thiocarbamoyl] imidazole (2.1 g, 8 mmol) and 2-(2-chlorophenyl)-ethylamine (1.25 g, 8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 100° C. for 1.5 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.6 g (57%) of the title product:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:28][CH2:29][OH:30])[CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:28][CH:29]=[O:30])[CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CCO)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)Cc1cn(C[C@@H](CC=O)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Yield: 84.6 %

Procedure:
To a solution of methyl [1-((2R)-2-{[(4-fluorophenyl)sulfonyl]amino}-4-hydroxybutyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]acetate (0.89 g, 1.9 mmol) in dichloromethane (16 mL) was added Dess-Martin reagent (0.99 g, 2.3 mmol, 1.2 equiv.). After a period of 45 min. the reaction mixture was purified directly by combiflash (20% ethyl acetate in hexane to 100% ethyl acetate) to give 697 mg of the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([OH:14])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:22][O:23][C:24]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[C:25]=1[NH2:26]>S(Cl)(Cl)=O.C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12]([NH:26][C:25]2[C:27]([O:33][CH3:34])=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:24]=2[O:23][CH3:22])=[O:14])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)Nc1c(OC)cc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
1.54 g (5 Mole) of the title compound of Example 3 in 20 ml of thionyl chloride was refluxed for 3 hours and then concentrated to dryness in vacuo. 523 mg (1.6 mmole) of the resulting acid chloride was dissolved in 20 ml methylene chloride and to the solution was added 292 mg (1.6 mmole) 2,4,6-trimethoxyaniline and 195 mg (1.6 mmole) 4-dimethylaminopyridine. The resulting solution was stirred at room temperature overnight and then concentrated in vacuo. The residue was partitioned between 60 ml ethyl acetate and 20 ml 1N aqueous hydrochloric acid solution. The ethyl acetate layer was washed with 50 ml water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on 100 g silica gel, eluting with 1:1 hexane/ethyl acetate to yield 370 mg (49% yield) of the title compound as a whitish solid.