Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:6]=[N:5][CH:4]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(Cl)Cl.CO>CN(C)C=O>[Si:18]([O:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:6]=[N:5][CH:4]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COc1ccccc1CCn1cncc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccccc1CCn1cncc1CO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
248 mg(1.09 mmol) of 5-hydroxymethyl-1-(2-methoxyphenethyl)-1H-imidazole prepared according to the same procedure as Preparation 9-1) was dissolved in 3 ml of dimethylformamide and 170 mg(1.13 mmol) of t-butyldimethylsilylchloride was added thereto. After stirring for 1 hour, the solvent was removed under reduced pressure and the residue was subjected to column chromatography(eluent: methylene dichloride/methanol=95/5, v/v) to give 248 mg(0.72 mmol, Yield 66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(O)(=O)C>[C:12]1(=[O:17])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=2)[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CCC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-(4'-aminophenyl)-propan-1-one (30 g, 0.2 mol), phthalic anhydride (60 g, 0.4 mol) and of acetic acid (300 ml) is heated at reflux for 2 h. The reaction mixture is cooled to room temperature and the precipitate consisting of 1-(4'-phthalimidophenyl)-propan-1-one (41 g, 0.150 mol, yield 75%) is filtered and dried in vacuo
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[I:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(I)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(I)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
30 g (108 mmol) of ethyl 6-iodonicotinate dissolved in 300 ml of ethanol are added dropwise to a solution of 20.5 g (542 mmol) of sodium borohydride in 200 ml of ethanol, cooled beforehand to 0° C. The reaction medium is allowed to warm to room temperature and is then stirred for 1 hour 30 minutes at room temperature. The reaction medium is hydrolysed and extracted with ethyl acetate. The boron salts precipitate out, and the medium is filtered and then evaporated to dryness. The reaction medium is taken up in dichloromethane, the product precipitates out, isopropyl ether is added and the medium is filtered. The precipitate is washed with isopropyl ether. 17 g (67%) of (6-iodopyrid-3-yl)methanol are obtained in the form of a pale yellow solid with a melting point of 102° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:17][O:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH:26][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:23][N:22]=1
Reactant: COCCc1nnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COCCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 114-115° C. and MS: m/e=338.2 (M+H+) was prepared in accordance with the general method of example 44a from 2,2-diphenylacetic acid chloride and [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.C[N:19]([CH3:22])C=O>ClCCl>[CH2:22]([NH:19][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-fluoro-5-nitrobenzoic acid (313 mg) in dichloromethane (4 mL) were added thionyl chloride (0.17 mL) and dimethylformamide (0.05 mL), and the mixture was heated for 36 hours under reflux. After evaporation of the solvent, the residue was dissolved in dichloromethane (4 mL). To this solution were added benzylamine (0.19 mL) and triethylamine (0.47 mL), and the mixture was stirred for 30 minutes at 0° C. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed successively with diluted hydrochloric acid, an aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The resulting residue was triturated with diisopropyl ether to give N-benzyl-2-fluoro-5-nitrobenzamide (436 mg) as a solid substance.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:19](OC)=[O:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].CO>C1COCC1>[CH2:1]([NH:8][C@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl N-benzyl-O-[tert-butyl(dimethyl)silyl]-D-serinate (1 eq.) in THF (0.4 M) at rt were added 2M LiBH4 in THF (1.2 eq.) and MeOH (1.2 eq). The mixture was stirred at rt for 16 hrs and quenched by the slow addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:4][C:3]1([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[OH:5]>CO.[Pt]=O>[CH3:1][C:2]1([CH3:12])[CH2:4][C:3]1([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)[OH:5]
Reactant: CC1(C)CC1(O)c1cnccn1
Agent: O=[Pt]
Solvent: CO
Product: CC1(C)CC1(O)C1CNCCN1
Yield: 97.9 %

Procedure:
A suspension of 2,2-dimethyl-1-(pyrazin-2-yl)cyclopropanol (1 g, 6 mmol) and platinum oxide (150 mg; 0.66 mmol) in methanol (15 ml) was shaken under a 60 psi H2 pressure using a PARR hydrogenator for 24 hours. The suspension was filtered over a celite pad and the filtrate was concentrated under reduced pressure to afford the title compound as a beige oil (1 g, 95%). 1H NMR (CD3OD) 0.90 (2H, s), 1.20-1.25 (6H, m), 2.45-2.50 (1H, m), 2.60-3.00 (5H, m), 3.30-3.40 (1H, m).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[N+](C1C=CC(C([O:39][C@H:40]2[C@@H:44]([NH:45][C:46]3[C:51]([CH2:52][CH3:53])=[N:50][C:49]([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=4[CH3:62])=[C:48]([CH2:63][CH3:64])[N:47]=3)[CH2:43][O:42][CH2:41]2)=O)=CC=1)([O-])=O>>[CH2:52]([C:51]1[C:46]([NH:45][C@H:44]2[CH2:43][O:42][CH2:41][C@H:40]2[OH:39])=[N:47][C:48]([CH2:63][CH3:64])=[C:49]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[CH3:62])[N:50]=1)[CH3:53]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1O

Procedure:
Following the procedure for the preparation of (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol, but substituting cis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-yl 4-nitrobenzoate and making non-critical variations provided the title compound as a colorless semi-solid. OAMS supporting ions at: ESI+ 358.2; MS (EI) m/z 357 (M+); HRMS (FAB) calcd for C20H27N3O3+H1 358.2130, found 358.2125.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(=NOC)c1cccc(Cl)c1CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1cccc(Cl)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.12 g, 3.0 mmol) was added to a solution of 3-chloro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.43 g, 1.68 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.44 g, 1.87 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about two hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 0.72 g crude oil. The oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentration gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-chloro-benzeneacetamide (430 mg) as an oil. (95% E isomer; 5% Z isomer).
Reaction SMILES: CSC.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)C1C=CC=CC=1.O>C(Cl)Cl>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[OH:11])=[CH:20][CH:21]=2)[CH2:26][CH2:27]1
Reactant: c1ccc(COc2ccccc2Cc2ccc(C3CC3)cc2)cc1
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: Oc1ccccc1Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 79.1 %

Procedure:
In a nitrogen stream, dimethyl sulfide (2.2 mL, 51.7 mmol) and a boron trifluoride-diethyl ether complex (1.1 mL, 8.8 mmol) were added to a solution of 1-benzyloxy-2-(4-cyclo-propylbenzyl)benzene (1.1 g, 3.5 mmol) in methylene chloride (24 mL) under cooling with ice, and the reaction mixture was stirred for 23 hours while gradually raising its temperature to room temperature. Water was added thereto under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:4)] to obtain the title compound (620.7 mg, 79%).
Reaction SMILES: [CH2:1]([S:8][C:9](SCC1C=CC=CC=1)=[C:10]([C:15]#[N:16])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][C:27](=[S:30])[NH:28][NH2:29]>C(O)C>[NH2:16][C:15]1[N:28]([C:27](=[S:30])[NH:26][CH3:25])[N:29]=[C:9]([S:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C#N)=C(SCc1ccccc1)SCc1ccccc1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CNC(=S)n1nc(SCc2ccccc2)c(C(=O)OC)c1N

Procedure:
45.11 g (0.127 mol) Methyl 3,3-dibenzylthio-2-cyanoacrylate and 13.35 g (0.127 mol) 4-methylthiosemicarbazide in 225 ml ethanol were heated under reflux for 10 hours. After cooling, the product was suction filtered, washed with ether and dried.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:17]([N:27]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](F)[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][F:54])[C@@H:11]1[CH3:57])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.CN1C[CH2:63][CH2:62][C:61]1=[O:65]>C(O)CC>[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:17]([N:27]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([O:65][CH2:61][CH2:62][CH3:63])[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:50][CH2:51][C:52]([CH3:56])([CH3:55])[CH2:53][F:54])[C@@H:11]1[CH3:57])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: CN1CCCC1=O
Reactant: C[C@H]1[C@H](OCC(C)(C)CF)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CCCOc1cc(F)cc(C[C@@H]([C@H](OCc2ccccc2)[C@H]2CO[C@@H](OCC(C)(C)CF)[C@H](C)N2C(=O)OC(C)(C)C)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Stir a mixture of sodium hydride (115 mg, 2.89 mmol, 60% in mineral oil) in N-methyl-2-pyrrolidinone (960 μL) and 1-propanol (234 μL) for 10 minutes and then add a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(3-fluoro-2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (440 mg, 0.57 mmol) in N-methyl-2-pyrrolidinone (1 mL) and stir in a sealed vial at 90° C. for 4 hours. Cool to room temperature and pour reaction mixture into water and extract well with ethyl acetate. Wash the organic phase with water followed by saturated aqueous sodium chloride and concentrate under reduced pressure. Subject the resulting residue to silica gel chromatography, eluting with hexane containing from 0-50% ethyl acetate to provide the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[C:5]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22](=[O:24])[CH3:23])[C:4]=2[N:3]=1.[C:25](OC)(=[O:28])[C:26]#[CH:27]>CO>[C:22]([NH:21][C:20]1[C:4]2[N:3]3[CH:27]=[CH:26][C:25](=[O:28])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[C:5]=2[CH:17]=[CH:18][CH:19]=1)(=[O:24])[CH3:23]
Reactant: C#CC(=O)OC
Reactant: CC(=O)Nc1cccc2c1N=C(N)CN=C2c1ccc(C#N)cc1
Solvent: CO
Product: CC(=O)Nc1cccc2c1-n1ccc(=O)nc1CN=C2c1ccc(C#N)cc1

Procedure:
In the manner given in Example 1, 2-amino-9-acetylamino-5-(p-cyanophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 11-acetylamino-7-(p-cyanophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:20][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)CCCCC>>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: c1ccc(C2CO2)cc1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CCCCCCO
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)c1ccccc1

Procedure:
A mixture of 3.14 parts of 2,2,6,6-tetramethylpiperidin-4-ol, 30 parts of styrene oxide and 30 parts of n-hexanol was heated at reflux for 18 hours. The n-hexanol solvent and unreacted styrene oxide were removed by distillation under reduced pressure. Crystallisation of the residue from cyclohexane gave 4.2 parts of 1-[2-hydroxy-2-phenylethyl]-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 123°C and the following elemental analysis by weight.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][NH2:61])=[CH:55][CH:54]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]>CN(C=O)C>[CH2:37]([N:39]([CH2:42][C:43]1[S:47][C:46]([C:48]2[O:52][N:51]=[C:50]([C:53]3[CH:54]=[CH:55][C:56]([CH2:59][CH2:60][NH:61][C:1](=[O:5])[CH2:2][OH:3])=[CH:57][CH:58]=3)[N:49]=2)=[CH:45][C:44]=1[CH3:62])[CH2:40][CH3:41])[CH3:38]
Reactant: O=C(O)CO
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CO)cc3)no2)cc1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of glycolic acid (15 mg, 202 μmol) and DIPEA (35 mg, 270 μmol) in DMF (5 mL) is added HOBt (27 mg, 202 μmol) and EDC hydrochloride (39 mg, 202 μmol) at 0° C. The mixture is stirred for 15 min at 0° C. Then 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine is added and stirring is continued for 1 h at 0° C. The reaction is quenched with water, diluted with sat. aq. NaHCO3 and the mixture is extracted three times with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (4 mg) as a colourless oil; LC-MS: tR=0.69 min; [M+1]+=429.06.
Reaction SMILES: C(OC([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+]>CO>[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:40][C:36]2[NH:37][CH:38]=[CH:39][N:35]=2)[CH:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(Cc3ncc[nH]3)C3CCCc4cccnc43)cc2)nc1
Reaction time: 40 h
Yield: 28.8 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (174 mg, 0.38 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (75 mg, 0.78 mmol) and sodium cyanoborohydride (55 mg, 0.88 mmol) and the mixture was stirred for 40 h. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 (30 mL) and aqueous 1 N sodium hydroxide (30 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 95:5) afforded the imidazole derivative (48 mg, 24%) as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[C:9]([NH:10][C:11]2[C:12]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N:25][C:13]=3[N:14]=[C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[F:24])[N:16]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:23][C:21]1[CH:20]=[CH:19][C:18]([F:24])=[C:17]([C:15]2[N:16]=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:35])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:12]3[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[N:25][C:13]=3[N:14]=2)[CH:22]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nc(NCCN(C)C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCNc1ccc2c(Nc3ccncc3C(=O)O)nc(-c3cc(Cl)ccc3F)nc2n1
Temperature: 25 °C

Procedure:
To a suspension of the ester, 4-[2-(5-Chloro-2-fluoro-phenyl)-7-(2-dimethylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ylamino]-nicotinic acid methyl ester (0.300 g) in MeOH (20 ml) was added a 1N NaOH (aq) (1.0 ml) and the reaction mixture was heated to reflux for 2 h. The solution was cooled to rt and concentrated in vacuo. Water (50 ml) was added to the crude material and the aqueous layer was acidified with HCl (1 N) and the mixture was placed in the freezer. The solid was filtered, washed with water and dried to give 4-[2-(5-Chloro-2-fluorophenyl)-7-(2-dimethylamino-ethylamino)-pyrido[2,3-d]pyrimidin-4-ylamino]-nicotinic acid as a cream colored solid. This material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH:10]([OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:10](=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2O)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
(±)-3-Hydroxy-4-(3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.27 g, 4.13 mmol) and pyridine (334 uL, 4 mmol) in methylene chloride (70 mL) at 0° C. were treated with Dess-Martin periodinane (3.5 g, 8.3 mmol) and then the reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of a mixture of sat. solution of Na2S2O3 and sat. solution of NaHCO3 (1:1 v:v) (50 ml), which was followed by extraction with ether. The product was isolated by flash chromatography to afford (±)-4-(3-methoxy-phenyl)-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.94 g, 75% yield). 1H NMR (CDCl3): δ ppm 7.27 (s, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.70-6.75 (m, 1H), 6.68 (s, 1H), 4.24 (d, J=18.2 Hz, 1H), 4.06 (d, J=18.2 Hz, 2H), 3.80 (s, 3H), 3.62 (dd, J=11.5, 5.9 Hz, 1H), 3.51 (br. s., 1H), 2.19-2.35 (m, 2H), 1.44-1.53 (m, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:24]2[CH2:28][C@H:27]([N:29]3[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]3)[C@@H:26]([OH:36])[C@H:25]2[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:16]=1)=[O:14].FC(F)(F)C(O)=O.O[C@@H]1[C@H](O)[C@@H](N2C=C(C)C=N2)C[C@H]1N1C=NC2C1=NC(NC1CCC(N[C:105]([NH:107][CH:108]3[CH2:113][CH2:112][N:111]([C:114]4[CH:119]=[CH:118][CH:117]=[CH:116][N:115]=4)[CH2:110][CH2:109]3)=[O:106])CC1)=NC=2NCC(C1C=CC=CC=1)C1C=CC=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:111]1([C:114]2[CH:119]=[CH:118][CH:117]=[CH:116][N:115]=2)[CH2:112][CH2:113][CH:108]([NH:107][C:105](=[O:106])[NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[C@@H:24]3[CH2:28][C@H:27]([N:29]4[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[N:30]4)[C@@H:26]([OH:36])[C@H:25]3[OH:37])=[C:17]([NH:38][CH2:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:16]=2)=[O:14])[CH2:109][CH2:110]1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NC1CCN(c2ccccn2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (3-amino-propyl)-amide trifluoroacetate (Example 63) using a procedure analogous to that of 1-{4-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-methyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-ylamino]-cyclohexyl}-3-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-urea trifluoroacetate (Example 42). MS (ES+) m/e 815 (MH+)