Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[CH:18]=[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:17])[C:11]3=[N:10]2)=[C:4]([Cl:19])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[CH:18]=[C:12]3[CH:13]=[N+:14]([O-:28])[CH:15]=[C:16]([F:17])[C:11]3=[N:10]2)=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cncc2cn(-c3c(Cl)cc(Br)cc3Cl)nc12
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(Br)cc3Cl)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
2-(4-Bromo-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine (14.5 g, 40 mmol) was suspended in DCM (160 mL), at 0° C. and meta-chloroperbenzoic acid (12.4 g, 72 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours then allowed to reach room temperature and stirred overnight. Additional meta-chloroperbenzoic acid (5 g, 30 mmol) was added and the reaction mixture was stirred at room temperature for another 3 hours. The resultant mixture was quenched with saturated aqueous sodium thiosulfate solution and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solid obtained was filtered and dried to afford the title compound as a beige solid (12.9 g, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (d, J=2.6 Hz, 1H), 8.88 (d, J=1.4 Hz, 1H), 8.33 (dd, J=6.3, 1.5 Hz, 1H), 8.19 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:16][C:17]1[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[CH3:22][C:20]1[O:21][C:17]([CH:16]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C=O)o1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccc(C)o1)C2=O

Procedure:
The title compound was prepared according to Method A3 from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 5-methyl-2-furaldehyde (192 mg, 2.0 mmol). ES-MS m/z 297 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH3:11])[CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Product: CN(CC[C@H]1CC[C@H](/C=C/CN2CCCCC2)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with piperidine in N,N-dimethylacetamide at room temperature to yield trans-methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 419 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:25]([NH:1][C@H:2]([CH:22]([CH3:24])[CH3:23])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)[C@H](N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)[C@H](NC(=O)c2ccccc2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of (R)-methyl 1-(2-amino-3-methylbutanoyl)-4-(4-chlorophenyl)piperidine-4-carboxylate (396 mg, 1.123 mmol) and benzoyl chloride (0.139 ml, 1.2 mmol) in CH2Cl2 (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.401 mL, 2.3 mmol). The mixture was stirred for 1 h at rt. The reaction was quenched with NaHCO3 (aq), extracted with dichloromethane, dried over Na2SO4 and concentrated. The residue was purified via column chromatography (20% EtOAc/heptane) to give (R)-methyl 1-(2-benzamido-3-methylbutanoyl)-4-(4-chlorophenyl)piperidine-4-carboxylate (467 mg, 91% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]([OH:38])[CH3:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH2:35][CH:36]([OH:38])[CH3:37])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-amino-2-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.5 (1H, br), 10.32 (1H, m), 8.54 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.08 (1H, s), 7.02 (2H, t, J=8.5 Hz), 4.88 (2H, m), 4.11 (2H, s), 4.05 (1H, m), 3.61 (1H, m), 3.51-3.44 (4H, m), 3.35 (1H, m), 2.20 (1H, d, J=4 Hz), 2.04 (2H, m, J=7 Hz), 1.89 (2H, m, J=7 Hz), 1.26 (3H, d, J=6 Hz); HRMS calcd for C25H27FN4O5+H+: 483.2044. Found: 483.2029.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCCOCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: ClCCCCCCCCCCOCc1ccccc1

Procedure:
A mixture of 7 g of 10-benzyloxy-1-decanol, 8 ml of thionyl chloride, and 0.2 ml of dimethylformamide was heated to 50° to 60° C. for one hour. After the reaction was over, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 50 ml of n-hexane, and after washing the solution with water, the solution was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off and the residue was applied to silica gel column chromatography and eluted with toluene to provide 6.7 g of oily 10-benzyloxy-1-chlorodecane. Boiling point 135°-140° C. (0.6-0.9 mm Hg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>ClCCl>[Si:30]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:10]2[CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[CH:9]2)=[CH:17][CH:16]=1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(-n2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a stirred mixture of 2-[4-(4-phenyl-1H-imidazol-1-yl)phenyl]ethanol (5.36 g, 20.3 mmol) and imidazole (2.7 g, 40.6 mmol) in dichloromethane (100 mL) was added TBSCl (3.67 g, 24.3 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 5:1 to 2:1) to afford 5.6 g (73%) of the title compound as white solids: 1H-NMR (CDCl3)δ0.00 (6H, s), 0.88 (9H, s), 2.87 (2H, t, J=6.6 Hz), 3.84 (2H, t, J=6.6 Hz), 7.26-7.30 (2H, m), 7.35-7.44 (5H, m), 7.54-7.55 (1H, m), 7.82 (1H, br), 7.85 (2H, d, J=1.2 Hz).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl.Cl.[NH2:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([F:37])=[CH:22][N:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](=[O:30])[NH:31][CH3:32])=[CH:25][C:20]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1F
Reactant: Nc1cnn(CC(=O)O)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1cc(Nc2cnn(CC(=O)O)c2)ncc1F
Temperature: 150 °C
Yield: 127.2 %

Procedure:
Reaction performed in 2 batches: Sodium tert-butoxide (773 mg, 8.05 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (0.478 g, 2.23 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 2-[(2-chloro-5-fluoropyridin-4-yl)amino]-N-methylbenzamide (250 mg, 0.90 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (82 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol) was added and the mixture was purged with nitrogen. The mixture was heated to 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. Both batches were combined and then evaporated. The residue was partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 by the addition of a 2N solution of HCl. The aqueous mixture was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL) and the resulting mixture filtered. The solid was washed with a 1:1 mixture of CH2Cl2/MeOH (3×150 mL) and the combined filtrates evaporated to afford 2-[4-[[5-fluoro-4-[[2-(methylcarbamoyl)phenyl]amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (440 mg, 64% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.79 (3H, d), 4.69 (2H, s), 6.70 (1H, d), 7.08 (1H, ddd), 7.33 (1H, s), 7.51 (1H, d), 7.55 (1H, ddd), 7.73 (1H, dd), 7.88 (1H, s), 7.93 (1H, d), 8.57 (1H, s), 8.70 (1H, q), 10.10 (1H, d); Mass spectrum: m/z (ESI+) (M+H)+=385.34.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]([C:22]([O:24]CC)=[O:23])[C:17]([O:19]CC)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]([C:22]([OH:24])=[O:23])[C:17]([OH:19])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1c2ccccc2CCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(C(=O)O)C1c2ccccc2CCc2ccccc21
Reaction time: 8 h

Procedure:
A solution of 305 g of crude diethyl 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonate and 138 g of potassium hydroxide in 1.5 l of ethanol and 400 ml of water is heated to boiling under reflux for 1.5 hours while stirring and subsequently evaporated in vacuo. The residue obtained is partitioned between 1 l of ether and 1 l of ice-water. The aqueous, alkaline phase is extracted further with 500 ml of ether, made acid with about 220 ml of concentrated hydrochloric acid while cooling with ice and extracted with 2 l of ether. The ethereal phase is washed three times with 500 ml of water each time and the aqueous washings are back-extracted with 1 l of ether. The combined ether extracts are washed for an additional three to four times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to a volume of about 400 ml. After dilution with 300 ml of petroleum ether, the clear solution obtained is cooled in an ice-bath and left to stand at 4° overnight. The crystallized-out material is removed by filtration under suction while back-washing with petroleum ether and dried at 50° in a vacuum drying oven. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-malonic acid of melting point 183° (with decarboxylation).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]2=[O:28])[CH:17]=[CH:18][CH:19]=1.C(I)C>CCCCCC.O1CCCC1.O>[CH2:1]([C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([OH:13])[CH:15]=2)[CH2:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[C:21]1=[O:28])[CH3:2]
Reactant: [Li]CCCC
Reactant: CN1CCCCC(c2cccc(O)c2)C1=O
Solvent: CCCCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Temperature: -10 °C

Procedure:
Butyl lithium (77 ml of a 1.4 molar solution in hexane) was added to a solution of diisopropylamine (14.8 ml) in dry tetrahydrofuran (20 ml) at -10° C. under nitrogen. The mixture was stirred at -10° C. for ten minutes and finely powdered hexahydro-3-(3-hydroxyphenyl)-1-methyl-2H-azepin-2-one (11 g) was added. Tetrahydrofuran (500 ml) was added and the mixture heated under reflux for 3 hours. After cooling, ethyl iodide (8.2 g) was added and the mixture again heated under reflux for 3 hours. Water (20 ml) was then cautiously added to the cooled solution and the mixture evaporated to a brown residue. After dissolving in water the mixture was extracted with dichloromethane and the dichloromethane extracted in turn with 2 M sodium hydroxide. The aqueous and sodium hydroxide washings were combined and acidified with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water, dried and recrystallised from ethyl acetate, affording 8.72 g of the title compound as white crystals, m.p. 178°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:21][O:22][C:23](=[O:28])[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH3:21])=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(OC)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(OC)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-(4-methoxy-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). ESI (m/z): 395 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=2)[NH:24]C(OC(C)(C)C)=O)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:43])[C@@H:12]([NH:21][C:22](=[O:42])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=2)[NH2:24])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cold solution of 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyryl-amino}-thiazole-4-carboxylic acid methyl ester (107 mg, 0.175 mmol) in dichloromethane (6 mL), was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 45 minutes, followed by removal of volatiles in vacuo. To the residue was added diethyl ether (10 mL) and the resulting suspension was separated by centrifugation. The solid was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-amino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester which was used immediately in the following step of the synthesis.
Reaction SMILES: CS(O)(=O)=O.C([O:13][CH2:14][C:15]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]1)C1C=CC=CC=1>C(Cl)Cl>[F:21][C:18]1([F:22])[CH2:17][CH2:16][C:15]([CH2:14][OH:13])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(COCc2ccccc2)CCC(F)(F)CC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CO)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Neat methanesulfonic acid (1.102 mL, 16.97 mmol) was added to a stirred solution of ethyl 1-((benzyloxy)methyl)-4,4-difluorocyclohexanecarboxylate (106 mg, 0.339 mmol) in DCM (2 mL) and the mixture was stirred at rt for 2 h. The reaction mixture was washed with water, satd. NaHCO3, brine and dried (MgSO4) to afford ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.25 (q, J=7.3 Hz, 2H), 3.67 (s, 2H), 2.28-2.17 (m, 2H), 2.08-1.93 (m, 2H), 1.86-1.80 (m, 2H), 1.67-1.56 (m, 2H), 1.31 (t, J=1.0 Hz, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[C:2]=[S:3].O.[NH2:15][NH2:16].C(OCC)(=O)C>CO.CCCCCC>[F:12][C:10]([F:11])([F:13])[C:6]1[CH:5]=[C:4]([NH:1][C:2]([NH:15][NH2:16])=[S:3])[CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NNC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-isothiocyanato-3-(trifluoromethyl)benzene (250 mg, 1.23 mmol) in methanol (5 mL) was added hydrazine hydrate (307 mg, 6.16 mmol) dropwise at 5° C.-10° C. After complete addition of hydrazine hydrate, the reaction mixture was stirred at room temperature for 2-3 h. When TLC (mobile phase-30% ethyl acetate in n-Hexane, Rf. S.M.—0.80, product—0.2) showed absence of starting material, the methanol was concentrated, water was added and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the pure product as an off white solid (Yield: 200 mg, 69.4% of theoretical).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCN1CCCCC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCCCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (450 mg, 1.61 mmol) in 2-propanol (40 mL) was added 2-(piperidin-1-yl)ethanamine (227 mg, 1.77 mmol) followed by triethylamine (160 mg, 1.58 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine. (Yield 411 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:15]([NH:22][C:4]1[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(C)c1n[nH]c2c(Cl)nc(Cl)nc12
Solvent: CCCCO
Product: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Yield: 96 %

Procedure:
5,7-Dichloro-3-isopropylpyrazolo[4,3-d]pyrimidine (1.015 mmol; 234.6 mg), 1 mL benzylamine and n-butanol (2 mL) were stirred at 65° C. for 4 hours. The reaction mixture was evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with the following solvent system: CHCl3/MeOH (99/1), to give 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine. Yield 96%; MS (ES+): 302.3 (100%, M+H+), 304.3 (32%, M+H+). 1H NMR (CDCl3; 300 MHz): 1.37 d (6H, J=7.1 Hz); 3.39 sept (1H, J=7.1 Hz), 6.72 s (1H), 4.82 s (2H), 7.28 m (5H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][S:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:50].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.C(Cl)Cl.CCOCC>[ClH:50].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[S:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2ccc(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis, see WO2004058144, Example 7(d) (64 mg, 0.33 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.13 g; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hours. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (60 mg) as the dihydrochloride salt.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)(C)=O.[C:9]1(/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:22]S(C)=O.C1COCC1>CS(C)=O>[CH2:20]([O:19][C:17]([C@@H:16]1[CH2:22][C@H:15]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)/C=C/c1ccccc1
Reactant: CS(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a stirred mixture of NaH (40.7 g) in DMSO (2.5 L) under N2 was added portion wise trimethyl sulfoxonium iodide (396 g, 1.80 mol, 1.76 equiv). A solution of 31 (180 g, 1.02 mol, 1.00 equiv) in 1:1 DMSO/THF (2 L) was added, and the reaction mixture was stirred at 25° C. overnight. The reaction mixture was quenched with 1N HCl (1 L) and extracted with EtOAc (2×2 L). The combined organic layers were washed with water (2×2 L) and brine (1×2 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (5 to 12.5% EtOAc) to afford 153 g (79%) of trans-ethyl-2-phenylcyclopropane-1-carboxylate (33) as a light yellow oil.