Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[C:19]([C@@H:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][C@H:21]([C:19]#[N:20])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O[C@H](C#N)c1cccc(Oc2ccccc2)c1

Procedure:
Following the procedure of Example 8, (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid and (S)-α-cyano-3-phenoxybenzyl alcohol are combined, in the presence of 4-dimethylaminopyridine and dicyclohexylcarbodiimide, to yield (S)-α-cyano-3-phenoxybenzyl (R)-2-(4-trifluoromethylphenylamino)-3-methylbutanoate, specific rotation=+62.1° (c=9 mg/ml in CHCl3).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:6](=O)[C:5]=12.[Li][CH:17]([Si](C)(C)C)[B:18]([O-:20])[O-:19].CN(CCN(C)C)C.[CH3:33][CH:34]1[CH2:39]CCN(C)[C:35]1([CH3:42])[CH3:41]>C1COCC1>[CH3:33][C:34]1([CH3:39])[C:35]([CH3:42])([CH3:41])[O:20][B:18](/[CH:17]=[C:6]2\[C:5]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]\2=3)[O:19]1
Reactant: [Li]C(B([O-])[O-])[Si](C)(C)C
Reactant: O=C1c2ccccc2CCn2cccc21
Reactant: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC1(C)OB(/C=C2/c3ccccc3CCn3cccc32)OC1(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Add one equiv of 5,6-dihydro-benzo[d]pyrrolo[1,2-a]azepin-11-one (prepared as described in Y. Girard, J. G. Atkinson, P. C. Belanger, J. J. Fuentes, J. Rokach, C. S. Rooney, D. C. Remy, C. A. Hunt J. Org. Chem. 1983, 48, 3220) in THF to a solution of 2.5 equiv of pinicol lithio(trimethylsilyl)methaneboronate (as described in D. S. Matteson, D. Majumder Organometallics 1983, 2, 230), 1 equiv TMEDA, 2.5 equiv of tetramethylpiperidine (TMP), and THF at −78° C. Allow the solution to warm to room temperature and stir for 3.5 h before quenching with excess water. Extract well with Et2O (4×). Dry (MgSO4) and concentrate under reduced pressure. Purify the crude residue by column chromatography (5% to 10% EtOAc:hexanes) to give pure E-isomer (45%) and
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[N+:19]=[N-:20])=[CH:14][CH:13]=1.IN1CCOCC1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:20]=[N:19][N:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=3)[C:10]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Agent: IN1CCOCC1
Product: COc1ccc(-c2nnn(-c3ccc(C)cc3)c2-c2ccccc2)cc1

Procedure:
Synthesized from 4-methoxy-phenylacetylene, 4-methyl-phenylazide, N-iodomorpholine and phenylboronic acid using one-pot/three-step general procedure, 1.19 g, 3.50 mmol, 70%; mp=192-195° C. (dec.); IR (υ[cm−1]) 3019, 2937, 1619, 1517, 1481, 1370, 1247, 1177, 1027, 997, 842, 820, 747; 1H NMR (600 MHz, CDCl3) δ=7.50 (d, J=8.4, 2H), 7.39-7.30 (m, 3H), 7.20-7.11 (m, 6H), 6.83 (d, J=8.5, 2H), 3.78 (s, 3H), 2.34 (s, 3H); 13C NMR (151 MHz, CDCl3) δ=159.5, 144.8, 139.2, 134.3, 133.1, 130.4, 129.9, 129.4, 129.2, 128.8, 128.2, 125.2, 123.6, 114.1, 55.4, 21.4; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C22H20N3O, 342.1601; found 342.1605.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[C:31](=[CH:20][C:3]2[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=2[CH3:1])[C:32](=[O:38])[NH:33]3)[CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 60.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (63 mg, 60.7%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C@@:6]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29]S(C2C=CC(C)=CC=2)(=O)=O)=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([S:29][C:3]2[C:4](=[O:20])[O:5][C:6]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH:8]([CH3:10])[CH3:9])[CH2:7][C:2]=2[OH:1])=[C:24]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1
Reactant: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(N)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 3.0 g (10.86 mmol) of (S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (prepared in Example WWWW), 3.98 g (11.40 mmol) of toluene-4-thiosulfonic acid S-(4-amino-2-tert-butyl-5-methyl-phenyl) ester (prepared in Example HHHH), 4.50 g of anhydrous K2CO3 and 54 mL DMF. The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated. The crude material was purified by flash silica gel chromatography, eluting with EtOAc, to give the title compound, m.p. 147°-149° C. (dec.). 1H-NMR (DMSO-d6) δ 0.89 (d, 3 H), 0.93 (d, 3 H), 1.42 (s, 9 H), 1.71 (s. 3 H), 1.85-1.93 (m, 2 H), 2.15 (m, 1 H), 2.41-2.50 (m, 2 H, partially obscured by DMSO), 2.67 (d of ABX q, 1 H), 2.89 (d of ABX q, 1 H), 6.55 (s, 1 H), 6.60 (s, 1 H), 6.64 (d, 2H), 6.93 (d, 2H), 9.13 (br s, 1 H).
Reaction SMILES: [NH2:1][C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH2:3][O:4][C:5](=[O:7])[CH3:6].CN(C)C1C=CC=CC=1.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>CCOCC.C(OCC)(=O)C>[C:5]([O:4][CH2:3][C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([NH:1][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCC(N)(COC(C)=O)COC(C)=O
Reactant: CCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(=O)CCCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-1,3-diacetoxy-2-octadecylpropane (1.0 g) was dissolved in 50 ml of dry ether and 425 mg of N,N-dimethylaniline and 500 mg of pentanoyl chloride were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried and the resultant mixture was concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→2:1) as an eluent to give 1.036 g of colorless, oily 1,3-diacetoxy-2-octadecyl-2-(N-pentanoylamino)propane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[N:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:54])([F:53])[F:52])[CH:41]=1>CCOC(C)=O.C(Cl)Cl>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]3[N:25]=[C:24]([N:26]([CH3:27])[CH3:28])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:12][CH2:13]2)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:53])([F:52])[F:54])[CH:41]=1
Reactant: CN(C)c1nc(NCC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1nc(NCC2CCN(S(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a suspension of 4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH2Cl2 (5 mL) was added diisopropylethylamine (480 μL, 2.76 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 3 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 14% to 20% EtOAc in hexane) to give N2-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (420 mg, 55%) as a yellow solid.
Reaction SMILES: [H-].[H-].COCCO[Al+2]OCCOC.C1(C)C=CC=CC=1.[CH2:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([NH2:30])=O)[CH3:22].Cl>O>[NH2:30][CH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:21][CH3:22]
Reactant: CCN1CCC[C@H]1C(N)=O
Agent: COCCO[Al+2]OCCOC
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCC[C@H]1CN
Temperature: 40 °C
Yield: 131.6 %

Procedure:
Bis (2-methoxyethoxy)aluminium dihydride (203.4 g, 0.70 mol, approx. 70% solution in toluene) and toluene (80 ml, dried over molecular sieves A) were added to a three-necked round-bottomed flask. The temperature in the flask was increased to 40° C. and then (S)-1-ethyl-2-pyrrolidinecarboxamide (21.0 g, 0.147 mol, 95% purity on GC) was added spoonwise during 45 min. In order to maintain the temperature at approx. 40° C., cooling was necessary during the addition. The temperature was decreased below 10° C. 55 min after completed addition. Water (500 ml) was added during 15 min and the pH was adjusted to 1 by adding 115 ml concentrated HCl and 100 ml H2O. After extraction, the phases were separated and 200 ml CH2Cl2 were added to the water phase. The pH was subsequently adjusted to 13-14 by adding NaOH (40%, 50 ml). The organic phase was separated and the water phase was extracted with further portions of CH2Cl2 (200+100 ml). The combined organic phases were dried, filtered and concentrated under vacuo to afford 24.8 g crude title product (83%) in an optical purity of >99%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[CH3:25])[C:16]3[C:12](=[N:13][N:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[C:15]=3[CH:26]([CH3:28])[CH3:27])[C:11]2=[O:37])[CH:9]=1)[C:5]#[N:6].Cl.[OH2:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[CH3:25])[C:16]3[C:12](=[N:13][N:14]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])[C:15]=3[CH:26]([CH3:28])[CH3:27])[C:11]2=[O:37])[CH:9]=1)[C:5]([NH2:6])=[O:39]
Reactant: O
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)cc(C#N)c1)C2=O
Agent: Cl
Product: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1C)N(c1cc(Cl)cc(C(N)=O)c1)C2=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of the compound prepared in example 103 (100 mg, 0.188 mmol) and concentrated HCl (10 mL) was heated to 70° C. and stirred at this temperature overnight. The reaction mixture was allowed to cool to rt, diluted with water and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and water, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH, 99:1) to afford the title compound. tR: 6.02 min (HPLC 2); ESI-MS: 549 [M+H]+ (LC-MS 2); Rf=0.47 (CHCl3/MeOH, 9:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[CH:4][C:5]#[N:6].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>C1(C)C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:4]([C:5]#[N:6])=[C:3]1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: CNC(=CC#N)c1ccc2ccccc2c1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc2ccccc2c1

Procedure:
A solution of β-(methylamino)-2-naphthaleneacrylonitrile (2.5 g, 0.012 mol) in toluene and acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (2.3 g, 0.012 mol) at room temperature, heated at reflux temperature for 6 hours, cooled and diluted with ethyl acetate. The organic phase is washed sequentially with water and 5N NaOH, dried (Na2SO4) and concentrated in vacuo to give a brown oil residue. The residue is flash chromatographed (silica gel, hexanes/ethyl acetate, 80/20) to give the title compound as a yellow solid, mp 134° C., identified by mass spectral, IR and NMR analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]([O:21]C)=[O:20])[O:10][C@@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:11]([C:19]([OH:21])=[O:20])[O:10][C@@H:9]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1O[C@H](c2ccc(OC)cc2)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc([C@H]2O[C@H](C(=O)O)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 93.7 %

Procedure:
33 mg (0.08 mmol) of (2R,4S,5S)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine, in suspension in 15 cm3 of methanol, are put, under an argon atmosphere, into a 50 cm3 round-bottomed flask equipped with a magnetic stirrer system. 5 cm3 of water and 33 mg (0.24 mmol) of potassium carbonate are then added. The mixture is allowed to react for 96 hours at a temperature in the region of 25° C. The reaction mixture becomes homogeneous. The methanol is removed under reduced pressure. The basic aqueous phase is diluted in 10 cm3 of water and then extracted with 3 times 15 cm3 of ether. The aqueous phase is cooled to 0° C. and is then acidified, with vigorous stirring in the presence of 20 cm3 of dichloromethane, with a 4M aqueous hydrochloric acid solution toga pH of less than 1. The acidic aqueous phase is extracted 8 times with 20 cm3 dichloromethane. The combined organic phases are washed with 3 times 5 cm3 of water and then once with 5 cm3 of a saturated aqueous sodium chloride solution. The organic phases are dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, there are obtained, with a yield of 94%, 30.0 mg (0.075 mmol) of (2R,4S,5S)-3-t-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:23][CH3:24])[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[C:13]2[CH:12]=[CH:11][CH:10]=1.[CH:25](=O)[CH2:26][CH3:27].S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1.C(OCC)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:23][CH3:24])[C:17]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[CH2:25][CH2:26][CH3:27])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1NCCOC
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCN(CCOC)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reaction time: 0.5 h

Procedure:
N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine (14 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.016 mL) and 3 M aqueous sulfuric acid (0.77 mL), sodium borohydride (5.8 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (9.5 mg) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]=[C:6]1[CH2:9][S:8][CH2:7]1)[CH3:2].[C:11]1([CH2:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:17]([NH:18][C:6]1([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH2:9][S:8][CH2:7]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C=C1CSC1
Reactant: NCc1ccccc1
Product: CCOC(=O)CC1(NCc2ccccc2)CSC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
A mixture of Thietan-3-ylidene-acetic acid ethylester (CAN 1223573-30-5, 1.8 g, 11.4 mmol) and phenylmethanamine (CAN 100-46-9, 1.22 g, 1.24 ml, 11.4 mmol) was stirred for 14 hours at ambient temperature. The crude product was directly purified without any work-up protocol. The crude material was purified by flash chromatography on silica eluting with a heptane-ethyl acetate gradient to yield the title compound (2.4 g, 80%). MS (ESI, m/z): 266.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 74.3 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.159 g of ethyl isocyanate according to the general procedure of Example 37 to give 0.86 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido-[2,3-d]pyrimidin-7-yl}-3-ethyl-urea, MS (ES+20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=517; mp 82°-90° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([Li])CCC.C1C[O:19][CH2:18]C1>>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH:18]=[O:19])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1cnc2[nH]ccc2c1
Reaction time: 1 h
Yield: 61 %

Procedure:
To 5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.5 g, 7.61 mmol) in THF (200 mL) at −78 C, under nitrogen, was added n-butyl lithium (2.5M in hexanes, 15.2 mmol, 6.1 mL), and the reaction solution was stirred with an overhead motor. After 1 hr, the resulting orange gel was quenched with methylormate (4.56 g, 76 mmol) and the reaction solution was allowed to slowly warm to 23C. The solution was poured into water and extracted with ethyl acetate, dried (Na2SO4) to give 1H-Pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.68 g, 61% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:15]>CCCCCCCCCCCC>[CH2:19]([O:18][C:16]([C:14]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1)=[O:17])[CH3:20]
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Reactant: CCOC(=O)C#N
Solvent: CCCCCCCCCCCC
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)ns1
Temperature: 150 °C
Yield: 30.6 %

Procedure:
To a solution of 5-(4-chlorophenyl)-[1,3,4]oxathiazol-2-one (0.60 g, 2.80 mmol) in n-dodecane (0.80 ml) was added ethyl cyanoformate (1.10 ml, 11.20 mmol). The resulting reaction mixture was refluxed for 20 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×75 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 20% EtOAc—Hexane) to get the product (0.23 g, 30%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1(C)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:21]C)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:1]([NH:5][S:6]([C:9]1([C:13](=[O:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)C1(C)CC1
Product: CC(C)(C)NS(=O)(=O)C1(C(=O)c2ccccc2)CC1
Yield: 66 %

Procedure:
This compound was obtained in 66% yield using the procedure described for the synthesis of N-tert-Butyl-(1-methyl)cyclopropylsulfonamide except 1.2 equivalents of methyl benzoate was used as the electrophile. The compound was purified by column chromatography over SiO2 using 30% to 100% CH2Cl2 in hexane: 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.52 (m, 2H), 1.81 (m, 2H), 4.16 (bs, 1H), 7.46 (m, 2H), 7.57 (m, 1H), 8.05 (d, J=8.5 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)O)=[CH:4][CH:3]=1.BrC1N=CC(C(OC)C2C3C(=NC=CC=3)NC=2)=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: COC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(Cc2c[nH]c3ncccc23)cn1
Yield: 86.8 %

Procedure:
A mixture of (6-bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (89, 1 g, 0.003 mol) and 3-[(6-bromo-pyridin-3-yl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (90, 2 g, 0.006 mol), triethylsilane (1 mL, 0.006 mol), and trifluoroacetic acid (0.5 mL, 0.006 mol) in acetonitrile (25 mL) was refluxed for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (91, 0.75 g, 60%). MS (ESI) [M+H+]+=288.06, 290.00.