Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:42][C:43]1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:44]=1[CH2:45][NH2:46]>O1CCCC1>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:41])[NH:11][CH:12]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]([OH:33])[CH2:14][N:15]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:46][CH2:45][C:44]3[CH:47]=[CH:48][C:49]([F:51])=[CH:50][C:43]=3[F:42])[CH:24]=2)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: NCc1ccc(F)cc1F
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(F)cc2F)c1
Yield: 100 %

Procedure:
{1-Benzyl-3-[(3-fluoro-4-nitro-benzenesulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester (7) (0.40 g, 0.67 mmol, 1 equiv) and 2,4-difluoro-benzylamine (0.14 g, 1 mmol, 1.49 equiv) were dissolved in tetrahydrofurane (10 mL). The solution was heated to reflux for 18 h. The solution was concentrated and the crude product was dissolved in dichloromethane (15 mL). The organic layer was washed with saturated NaHCO3 solution (15 mL). The organic layer was separated and evaporated under reduced pressure to yield the title compound (0.48 g, 0.67 mmol, quantitative). LRMS (ES+): m/z 719 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][C:8](=O)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2].CO>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][N:7]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C)OCC(=O)N1Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C1C(C)OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-benzyl-2-methyl-5-oxo-morpholine-3-carboxylic acid ethyl ester (0.24 g, 0.865 mmol; prepared according to the procedure described in Meinzer A. et al., Helv. Chim. Acta 2004, 87, 90-105) in tetrahydrofuran (7 ml) was cooled to −20° C. and borane-methyl sulfide complex (0.246 ml, 2.595 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. After the addition of methanol (5 ml), stirring was continued for 1 h. The solution was diluted with dichloromethane, washed with brine, and concentrated in vacuo. The resulting 4-benzyl-2-methyl-morpholine-3-carboxylic acid ethyl ester was used in the next step without further purification. LC/MS (method 8): Rt=0.54 min; m/z=264.25 (M+H+).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11](O)=[O:12]>CN(C=O)C.C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH:10]([C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1)[C:11]([Cl:4])=[O:12]
Reactant: O=C(O)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g) in methylene chloride (30 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride. A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride in THF (5 mL) was added to a solution of tert-butyl carboxylate (600 mg) and triethylamine (3.1 mL) in THF (20 mL) at 0° C., and the reaction solution was stirred at room temperature for one hour. The reaction solution was added to a saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.35 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:6]
Reactant: CC(C)N
Reactant: O=C(O)c1cc(F)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1cc(F)ccc1F

Procedure:
The title compound was prepared from 2,5-difluorobenzoic acid (10 g, 63.2 mmol), carbonyldiimidazole (9.57 g, 61 mmol) and isopropyl amine (5.15 mL, 60.5 mmol) according to the procedure used for example 84 (Step A) to give near quantitative yield of the title compound.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1.O>C1COCC1>[Br:29][C:14]1[C:15]2[C:20]([C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
4 g (1 eq, 14.9 mmol) of 9-p-tolyl-anthracene, 5.3 g (2 eq, 29.8 mmol) of NBS were dissolved in 200 ml of THF in a 500-ml round-bottomed flask and stirred for 1 hour. 200 ml of water was added to the solution to obtain yellow crystals. The yellow crystals were filtered, dissolved in a small amount of toluene, and separated using column chromatography (silica and hexane) to obtain 4.6 g (89%) of yellow crystals.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].CCO.CCN(C(C)C)C(C)C.Cl[C:44]1[S:45][C:46]([C:49]#[N:50])=[CH:47][N:48]=1>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:44]2[S:45][C:46]([C:49]#[N:50])=[CH:47][N:48]=2)[CH2:4]1)[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CC[C@@H]1C[C@H](Nc2ncc(C#N)s2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 150 °C
Yield: 83.9 %

Procedure:
A mixture of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.20 g, 0.47 mmol), EtOH (1.3 mL), DIEA (0.33 mL, 1.88 mmol), and 2-chlorothiazole-5-carbonitrile (0.082 g, 0.56 mmol, Ark Pharm) was heated in a CEM microwave at about 150° C. for about 30 min (250 psi maximum pressure, 5 min maximum ramp, 300 maximum watts). The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The crude oil was dissolved in DCM (10 mL) and washed with water (2×10 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude mixture was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to give 2-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)thiazole-5-carbonitrile (0.21 g, 84%): LC/MS (Table 1, Method c) Rt=1.53 min; MS m/z: 533 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[C:27]([CH3:32])=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][N:29]1[CH:30]=[C:26]([CH2:25][N:22]2[CH2:21][CH2:20][N:19]([C:14]3[C:13]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:24][CH2:23]2)[C:27]([CH3:32])=[N:28]1
Reactant: Cc1nn(C)cc1CN1CCN(c2nccnc2Cl)CC1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nn(C)cc1CN1CCN(c2nccnc2-c2ccc(Cl)c(F)c2)CC1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
Add 4-chloro-3-fluorobenzeneboronic acid (125 mg, 0.72 mmol) to a nitrogen purged solution of 3′-chloro-4-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (200 mg, 0.65 mmol) in dry N,N-dimethylacetamide (4 mL) and deoxygenated water (2 mL). Add potassium carbonate (215 mg, 1.72 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.004 g, 0.0035 mmol) and stir at 110° C. for 6 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3×20 mL). Concentrate the combined DCM extracts and purify by reverse phase HPLC to give the title compound (0.036 g, 14%). MS (ES): m/z=401 [M+H]+
Reaction SMILES: C(OC([NH:8][C:9]1[C:14](I)=[C:13]([CH3:16])[N:12]=[CH:11][N:10]=1)=O)(C)(C)C.[Br-].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Zn+])=[CH:22][CH:21]=1.O1CCCC1.FC(F)(F)C(O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[NH2:8][C:9]1[C:14]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:21][CH:22]=2)=[C:13]([CH3:16])[N:12]=[CH:11][N:10]=1
Reactant: Cc1ncnc(NC(=O)OC(C)(C)C)c1I
Reactant: FC(F)(F)c1ccc(C#C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
4-(tert-Butoxycarbonylamino)-5-iodo-6-methylpyrimidine and {4-(trifluoromethyl)phenyl]ethynylzinc bromide were reacted in a solvent mixture of tetrahydrofuran and N,N-dimethylformamide (1:1) in the presence of tetrakis(triphenylphosphine)palladium while stirring under room temperature to heating to obtain a compound. To the compound, trifluoroacetic acid was added to remove a tert-butoxycarbonyl group serving as a protecting group to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]2[N:27]([CH3:30])[N:28]=[CH:29][C:15]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:17][C:16]2[N:27]([CH3:30])[N:28]=[CH:29][C:15]1=2
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.95 g, 18.1 mmol), tert-butyl 4-hydroxy-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 135 (US2005/245505 A1, 2.29 g, 9.04 mmol) and triphenylphosphine (4.74 g, 18.1 mmol) in THF (100 mL) was added DIAD (3.85 mL, 19.9 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 136 (2.5 g, 35%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.C1(C2NCC3C=CC(OC4C=CC(C#N)=CN=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: N#Cc1ccc(Oc2ccc3c(c2)CCC(C2CCC2)NC3)nc1
Product: CC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 214 (E214) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 1-(6-chloropyridin-3-yl)ethanone using the method described for Example 100 (E100); MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2].C1C(=O)N([Cl:23])C(=O)C1>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][N:6]1[C:14]([Cl:23])=[C:13]2[C:8]([N:9]=[CH:10][CH:11]=[CH:12]2)=[N:7]1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1cc2cccnc2n1
Solvent: ClCCl
Product: CCOC(=O)Cn1nc2ncccc2c1Cl
Temperature: 25 °C

Procedure:
To a solution of pyrazolo[3,4-b]pyridin-2-yl-acetic acid ethyl ester 57 (40.2 Mg, 0.2 Mmol, 1 equiv) in 1 mL of dichloromethane was added NCS (32.7 Mg, 1.2 Mmol, 1.2 equiv). The resultant mixture was heated at 70° C. for 30 min., cooled to room temperature, and diluted with 100 mL of dichloromethane. The organic solution was washed with 50 mL of saturated sodium bicarbonate aqueous solution, and 50 mL of brine. The organic layer was separated and dried over sodium sulfate. Evaporation of solvent in vacuo gave 46.7 Mg of (3-chloro-pyrazolo[3,4-b]pyridin-2-yl)-acetic acid ethyl ester as yellow solid.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5](CO)=[CH:4][C:3]=1[C:10]([Cl:14])=[C:11]([Cl:13])Cl.[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([Cl:38])(Cl)(Cl)[Cl:35]>>[CH3:15][C:8]1[CH:9]=[CH:2][C:3]([CH:10]([Cl:14])[C:11]([Cl:13])=[C:34]([Cl:38])[Cl:35])=[CH:4][CH:5]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(CO)cc1C(Cl)=C(Cl)Cl
Product: Cc1ccc(C(Cl)C(Cl)=C(Cl)Cl)cc1

Procedure:
A solution of 4-methyl-3-(trichlorovinyl)benzyl alcohol (2.06 g) and triphenylphosphine (2.58 g) in 100 ml of carbon tetrachloride was heated at reflux for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in CH2Cl2 (200 ml). This organic solution was shaken with 30% H2O2 (10 ml) and then diluted with water (100 ml) and the layers separated. The organic layer was further washed with water, dried with anhydrous magnesium sulfate and concentrated to give 4.37 g of crude product. Chromatography on silica (1:1 hexane:methylene chloride) gave 1.81 g of 4-methyl-(trichlorovinyl)benzyl chloride.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1)C.[BH4-].[Li+].O>C1COCC1>[Br:13][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(Br)nc1

Procedure:
Under argon, 560 mg (2.17 mmol) of 3-(6-bromopyridin-3-yl)propionic acid ethyl ester and 94.6 mg (4.34 mmol) of lithium borohydride were stirred in 40 ml of THF at 40° C. for 3 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and the filtrate was concentrated and admixed with water and ethyl acetate. The organic phase was separated, washed with water and concentrated. Yield: 450 mg (96%).
Reaction SMILES: [OH-].[Na+].O.C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC([C:22]([C@:24](C(O)=O)([OH:39])[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=[O:23])=CC=1.[F:44][C:45]1[C:50]([C@@H:51]([NH:53][CH2:54][C@@H:55]([OH:57])[CH3:56])[CH3:52])=[CH:49][CH:48]=[C:47]([F:58])[N:46]=1>C1(C)C=CC=CC=1>[F:44][C:45]1[C:50]([C@@H:51]([N:53]2[CH2:54][C@H:55]([CH3:56])[O:57][C:22](=[O:23])[C:24]2=[O:39])[CH3:52])=[CH:49][CH:48]=[C:47]([F:58])[N:46]=1
Reactant: C[C@H](O)CN[C@@H](C)c1ccc(F)nc1F
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN([C@@H](C)c2ccc(F)nc2F)C(=O)C(=O)O1
Temperature: 145 °C
Reaction time: 3 h
Yield: 115.4 %

Procedure:
A 5 N sodium hydroxide aqueous solution (450 mL), water (1000 mL), and 50% toluene-THF (2000 mL) were added to (S)-1-[(S)-1-(2,6-difluoropyridin-3-yl)ethylamino]propan-2-ol (+)-di-p-toluoyl-D-tartrate (199 g). The organic layer was separated. The water layer was extracted with 50% toluene-THF (800 mL) three times. All the organic layers were combined and concentrated under reduced pressure. To the residue, diethyl oxalate (200 mL) was added. The resulting reaction solution was heated to and stirred at 140 to 150° C. After 3 hr, the reaction solution was diluted with toluene (500 mL) and cooled with ice while stirring. The precipitated crystal was filtered, washed with toluene and diethyl ether, and dried in air to give 103 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=2)[C@H:4]([CH3:18])[CH2:3]1.[CH2:19]([Li])[CH2:20][CH2:21]C.Cl.C1C[O:28]CC1>>[CH3:16][CH:15]([O:14][C:10]1[CH:9]=[C:8]([C@@:5]23[CH2:6][C@H:7]([CH2:19][C:20](=[O:28])[CH2:21]2)[N:2]([CH3:1])[CH2:3][C@H:4]3[CH3:18])[CH:13]=[CH:12][CH:11]=1)[CH3:17]
Reactant: [Li]CCCC
Reactant: CC(C)Oc1cccc(C2=CCN(C)C[C@H]2C)c1
Reactant: C1CCOC1
Agent: Cl
Product: CC(C)Oc1cccc([C@]23CC(=O)C[C@@H](C2)N(C)C[C@H]3C)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (S)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine (14) (1 eq) dissolved in THF (20 mL/g) and cooled to −10° C. was added n-butyl lithium (1.6M in hexanes) slowly until a red color is maintained followed by an addition of 1.1 eq. This material is stirred for 1 h at 10° C. and then cannulated quickly into a solution of Okahara's reagent (distilled to high purity) in THF (15 mL/g, 1.1 eq) at −78° C. followed by stirring for 2 h. The temperature should be kept below −30° C. during cannulation. This material is then poured into 2N HCl and extracted twice with ethyl ether. The aqueous layer is allowed to stand for 15 min followed by addition of 50% NAOH to pH 14 and extraction (3×) with ethyl ether. The ether is then washed (1N NaOH, H2O) and the solvent removed under vacuum. The resulting residue of product and water is dissolved in MeOH (30 mL/g) and nitrogen is bubbled through the solution for 5 min. To this is added concentrated HCl (2 mL/g), and the mixture is allowed to stand at room temperature until the reaction is complete as indicated by TLC (TLC condition: SiO2; elution with 50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3. Detection: 5% phosphomolybdic acid in ethanol. To this mixture was added 50% NaOH to adjust the pH to ˜10 and the methanol is removed under aspirator vacuum. The aqueous residue is then extracted several times with 3:1 (methylene chloride:THF). The organic extracts are combined and washed twice with water and once with brine, dried over sodium sulfate and evaporated to an oil. This material was purified by flash chromatography on silica gel using 25-50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3 to give 15 in 70% yield from 14. 1H NMR 7.24 (t,1,J=7.5 Hz), 6.77 (m, 3), 4.55 (m, 1), 3.49 (s, 1), 2.91 (dd,2,J=17 Hz and 16.5 Hz), 2.60 (m, 2), 2.35 (m, 5), 2.05 (m, 3), 1.35 (m, 6), 0.78 (d,3,J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[I-].[Na+].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.CCOCC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14](=[O:18])[CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C(=O)CCCl)c2c1NC(=O)CC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
26.8 Grams of 8-methoxy-5-(3-chloropropionyl)-3,4-dihydrocarbostyril and 16.5 g of sodium iodide were dissolved in 200 ml of dimethylformamide and the mixture was stirred at 40° C. for 1 hour. Then 11.1 g triethyl amine and 17.1 g of 4-phenylpiperazine were added to the mixture and stirred at 40° C. for 2 hours additionally. The reaction mixture was concentrted under a reduced pressure to obtain a residue. Then a 5%-sodium hydrogencarbonate aquous solution and ether were added to the residue to obtain crystalline presipitates. The precipitates were collected by filtration and were recrystallized from ethanol to obtain 8-methoxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>O.[Pt-]=O.CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2
Reactant: OCc1ccc2ncccc2c1
Agent: O=[Pt-]
Solvent: O
Solvent: CO
Product: OCc1ccc2c(c1)CCCN2
Reaction time: 2 h
Yield: 68.7 %

Procedure:
6-Hydroxymethylquinoline (1 g, 6.28 mmoles) (prepared by the method of: C. E. Kaslow and W. R. Clark, J. Org. Chem., 1953, 18, 55-58.) and methanol (200 mL) were placed in a Parr bomb and platinum (I) oxide monohydrate (0.5 g, 2.04 mmoles) was added. The mixture was hydrogenated at 50 psi at 25° C. for 2 h. The catalyst was filtered off and washed with methanol. The combined filtrates were evaporated to dryness and the product was chromatographed on silica gel using 1.5% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.7044 g, 68%): CIMS: m/z 164.35 (MH+); 6. (CDCl3) 1.93 (2H, m, 3-CH2) and 2.76 (2H, t, 4-CH2), 3.30 (2H, m, 2-CH2), 4.50 (2H, s, CH2OH), 6.45 (1H, d, Ar—H8), 6.96 ppm (2H, m, Ar—H5 and Ar—H7); δC (CDCl3) CH2: 22.1, 27.0, 42.0, 65.6; CH: 114.2, 126.4, 129.2; C: 121.5, 129.4, 144.5.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[N:6]=[C:7]2[S:22][CH:21]=[C:20]([CH3:23])[N:8]2[C:9](=[O:19])[C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)[CH3:4].[F:24][C:25]1[N:33]=[C:32]2[C:28]([NH:29][CH:30]=[N:31]2)=[C:27](Cl)[N:26]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:18][C:13]1[CH:12]=[C:11]([C:10]2[C:9](=[O:19])[N:8]3[C:20]([CH3:23])=[CH:21][S:22][C:7]3=[N:6][C:5]=2[CH:3]([NH:2][C:27]2[N:26]=[C:25]([F:24])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:4])[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3nc(F)nc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 100 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one hydrochloride (0.030 g, 0.084 mmol), 2-fluoro-6-chloropurine (0.015 g, 0.084 mmol), and N,N-diisopropylethylamine (0.044 mL, 0.25 mmol) in isopropyl alcohol (0.2 mL) was heated at 100° C. for three days, in a sealed tube. The resultant mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product. LCMS calculated for C20H15F3N7OS (M+H)+: m/z=458.1. Found: 458.0.