Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[C:10]([CH:11]=[O:12])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>C1(C)C=CC=CC=1>[NH2:1][C:9]1[C:10]([CH:11]=[O:12])=[C:5]([Cl:4])[N:6]=[CH:7][N:8]=1
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: N
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1ncnc(Cl)c1C=O
Temperature: 23 °C
Reaction time: 3.5 h

Procedure:
A solution of 7 M NH3 in MeOH (265 mL, 1.855 mol, 2.0 equiv) was added over 1.25 h to a solution of 4,6-dichloropyrimidine-5-carbaldehyde (163.7 g, 0.9301 mol) in toluene (3 L) at ambient temperature. The reaction temperature slowly increased from 20 to 26° C. and a yellow suspension formed. Mild cooling was applied to maintain the reaction temperature at below 26° C. The suspension was stirred at ambient temperature for 3.5 h before the solids were collected by filtration. The solids were washed with EtOAc (1 L). The filtrate was concentrated under reduced pressure, and the solids were triturated with toluene and n-heptane (2:1 v/v, 600 mL), filtered and dried to give 71.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The original solid filtered from the reaction mixture contained additional amount of 4-amino-6-chloropyrimidine-5-carbaldehyde. The product was extracted from the filtered solid by stirring in EtOAc (1.25 L) for 1.5 h, filtering, then stirring in THF (750 mL) for 1 h and again filtering. Both EtOAc and THF filtrates were concentrated under reduced pressure, and the resulting solids were triturated with toluene and n-heptane (2:1 v/v, 450 mL), filtered and dried to give an additional 44.1 g of 4-amino-6-chloropyrimidine-5-carbaldehyde as a yellow solid. The combined yield of 4-amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 146.5 g theoretical) was 78.6%. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.71 (bs, 1H), 8.55 (bs, 1H), 8.39 (s, 1H) ppm; C5H4ClN3O (MW, 157.56), LCMS (EI) m/e 158 (M++H).
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7]([OH:9])=O.[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7](=[O:9])[CH2:1][CH3:2]
Reactant: [Li]CC
Reactant: CC(C=CCC(C)CCCC(C)(C)C)=CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 9.5 ml. of a one molar solution of ethyllithium in benzene and 50 ml ether, under nitrogen is added at 0° 1.0 g. of 3,7,11,11-tetramethyldodeca-2,4-dienoic acid in 10 ml. ether. The reaction mixture is stirred for three hours and then is poured into a rapidly stirred saturated aqueous ammonium chloride solution followed by the addition of 50 ml. of ether. The organic layer is separated and then is washed with saturated sodium chloride. The solution is dried over magnesium sulfate and the solvent is removed to yield 5,9,13,13-tetramethyltetradeca-4,6-dien-3-one.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:17]CC)=[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:24][CH:23]=[CH:22][CH2:21]1>>[CH2:1]([C:8]1[C:22]2[CH2:21][O:20][CH2:24][C:23]=2[C:10]([OH:17])=[C:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: CCOc1oc(Cc2ccccc2)nc1CC(C)C
Product: CC(C)Cc1nc(Cc2ccccc2)c2c(c1O)COC2

Procedure:
2-Benzyl-4-isobutyl-5-ethoxyoxazole is reacted with 2,5-dihydrofuran, using the method described in Example 22. 38 g of crude 4-benzyl-6-isobutyl-1,3-dihydro-furo[3,4-c]pyridine-7-ol are obtained. Recrystallization from ethyl acetate gives a pure product, melting point 174°-175° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH:17]3[CH:22]=[CH:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]3)=[C:12]([F:25])[CH:11]=2)[CH2:5]1.[F:26][CH:27]([F:33])[C:28](OCC)=[O:29].C(N(CC)CC)C>CO>[O:24]=[S:20]1(=[O:23])[CH:19]=[CH:18][CH:17]([C:13]2[C:14]([F:16])=[CH:15][C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:28](=[O:29])[CH:27]([F:33])[F:26])[O:8][C:7]3=[O:9])=[CH:11][C:12]=2[F:25])[CH2:22][CH2:21]1
Reactant: NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCOC(=O)C(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(F)F
Yield: 80.9 %

Procedure:
(5S)-5-(aminomethyl)-3-[4-(1,1-dioxido-3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one monohydrochloride from Step 1 (0.400 g, 1.02 mmol), ethyl difluoroacetate (0.633 g, 5.1 mmol), and triethylamine (0.284 ml, 2.04 mmol) in methanol (8 ml) were stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give white solid (0.36 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[N:46]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:33]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([C:38]3[N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.71 g, 1.3 mmol) to give, after chromatography on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05, the title compound: Rf=0.85 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 60 °C
Yield: 12.6 %

Procedure:
A mixture of 4-(piperidin-4-yl)aniline hydrochloride (14.10 mmol, 3 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14.10 mmol, 4.75 g) and potassium carbonate (42.3 mmol, 5.85 g) in acetonitrile was heated to 60° C. (heating block temperature) for 20 hours. The reaction was concentrated under reduced pressure and dichloromethane was added. The mixture was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (770 mg). MS (ESI) m/z 433.3 [M+H]+
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([NH:16][C:18](=[O:22])[CH2:19][CH2:20][CH3:21])=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(-c2nc3cc(N)ccc3s2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc2sc(-c3ccc(C)cc3)nc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
To a solution of 2-p-tolylbenzo[d]thiazol-5-amine (110 mg, 0.46 mmol) in pyridine (3 mL) at room temperature was added butyryl chloride (53 μL, 0.50 mmol). The resulting mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate, followed by aqueous sodium bicarbonate and finally with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 25 mg (18%) of the title compound (LCMS RT=7.10 min, MH+ 311.0)
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C@@:25]2([CH3:26])[C@H:23]([O:24]2)[CH2:22][C@@H:21]([OH:27])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.Cl[Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36]>CN(C)C=O.O>[C:14]([Si:1]([O:18][C@@H:19]1[CH2:20][C@H:21]([O:27][Si:34]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:35][CH3:36])[CH2:22][C@@H:23]2[C@@:25]1([CH3:26])[O:24]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H](O)C[C@H]2O[C@]21C)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H]1C[C@H]2O[C@@]2(C)[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Yield: 90 %

Procedure:
The compound of Example 13B (16.0 g, 42 mmol) was dissolved in 20 mL of dimethylformamide; 7.1 g of imidazole (100 mmol, 2.5 equivalents) was added, followed by 10.5 mL of chlorotriethylsilane. The resultant mixture was stirred overnight at ambient temperature, then was diluted with water and extracted with ethyl acetate. The organic phase was concentrated washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was purified by flash chromatography, eluting with a gradient from 50% to 100% dichloromethane in hexanes to provide the titled compound (14.0 g, 90%).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](OC(N)C)=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[C:31](=[O:33])[CH3:32])(=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:9][CH2:8][CH2:7][NH:21][C:31](=[O:33])[CH3:32])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)NCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 141.7 %

Procedure:
To a mixture of [(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethanamine (0.58 g, 1.68 mmol) in DMF (10 mL) is added acetic anhydride (0.17 g, 1.68 mmol) and DMAP (0.01 g, 0.082 mmol). The mixture is heated at 85° C. for 45 min, then partitioned between water and ether. The organic layer is washed twice with water, dried over magnesium sulfate and concentrated. Column chromatography (70 g silica gel) using CH2Cl2/acetone (80/20) as eluent gave 0.46 g (71%) of N-{2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]ethyl}acetamide.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CN(C)C=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: ClCCCBr
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: ClCCCn1cncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A 1,2,4-triazole sodium salt (5 g, 54.91 mmol) was dissolved in dimethylformamide (50 mL) and the solution was cooled to 0° C. Then, sodium hydride (60%, 2.86 g, 71.38 mmol) was added thereto, followed by stirring for 30 minutes. 1-bromo-3-chloropropane (6.5 mL, 65.89 mmol) was added thereto, followed by stirring at room temperature for 12 hours, and the reaction was terminated with the addition of an ammonium chloride saturated solution. After extraction with ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (2.77 g, 35%).
Reaction SMILES: [NH3:1].CO.[C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]=[C:21]([C:23]([O:25]C)=O)[CH:20]=[C:19]([CH:27]=[CH2:28])[N:18]=3)=[CH:13][CH:12]=2)=[CH:8][C:7]=1[C:31]([F:34])([F:33])[F:32])#[N:5]>CO>[C:4]([C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[C:21]([C:23]([NH2:1])=[O:25])[CH:20]=[C:19]([CH:27]=[CH2:28])[N:18]=3)=[CH:15][CH:16]=2)=[CH:8][C:7]=1[C:31]([F:33])([F:34])[F:32])#[N:5]
Reactant: N
Reactant: C=Cc1cc(C(=O)OC)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Solvent: CO
Product: C=Cc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)cc2)n1
Temperature: 25 °C

Procedure:
In a 50-mL vial with a screw-top septum, methyl 2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxylate was dissolved in MeOH (2 mL) and stirred at room temperature. To the solution was added 7N NH3/MeOH (5 mL) and the reaction mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure and purified using Combiflash with a gradient of methanol (30% max) in chloroform to provide 2-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-6-vinylpyrimidine-4-carboxamide (270 mg) as a white solid. LC/MS: m/z=411 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1(c2ccccc2)CCCCCC1
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCCCCC1

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (Example 1c) (4.15 g) was refluxed in methanol (150 mL) and concentrated hydrochloric acid (5 mL) for 24 hours. The solvent was evaporated and the residue was dissolved in ether (100 mL) which was washed with water (100 mL), saturated sodium bicarbonate (50 mL) and water (100 mL), dried (MgSO4) and evaporated to afford the sub-titled compound (3.5 g) as an oil.
Reaction SMILES: [NH:1]([C:8]1[C:18](=[O:19])[C:12]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10](=[O:20])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[NH:1]([C:8]1[C:18](=[O:19])[C:12]2[N:13]=[C:14]([CH2:16][CH3:17])[O:15][C:11]=2[C:10](=[O:20])[C:9]=1[Cl:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nc2c(o1)C(=O)C=C(Nc1ccccc1)C2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CCc1nc2c(o1)C(=O)C(Cl)=C(Nc1ccccc1)C2=O
Reaction time: 2 h

Procedure:
A solution of 5-anilino-2-ethyl-1,3-benzoxazole-4,7-dione (1 eq.) in acetic acid is treated with N-chlorosuccinimide (1.1 eq.) at ambient temperature. The reaction medium is maintained under stirring for 2 hours before being concentrated, followed by taking up in ethanol and concentrating again. The residue is purified by medium pressure chromatography on silica in order to produce a violet-coloured powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:10][C:11]1[C:16]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Brc1ccccn1
Reactant: OCc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1Br
Temperature: 25 °C
Yield: 93.1 %

Procedure:
Add 85% manganese(IV) oxide (500 g, 5.75 mol) to a slurry of (2-bromopyridine)-(2-chlorophenyl)-methanol (392 g, 1.131 mol) in toluene (2.5 L), heat to a reflux and stir. After one hour cool to ambient temperature and filter through Celite®. Concentrate the solution under reduced pressure. Purify by recrystalization from MTBE: heptane (2:1) to give title compound 312.4 g (80%). 1H NMR (300 MHz, CDCl3), δ 8.50 (dd, 1H, J=1.83, 4.73), 7.78 (dd, 1H, J=1.83, 7.63), 7.60 (dd, 1H, J=1.53, 7.63), 7.53-7.34 (m, 4H); MS (IS) m/z 296.0 (M+1), 298.0 (M+1); m.p.=76.3° C.; Analysis for C12H7BrClNO: calcd: C, 48.60; H, 2.38; N, 4.72; found: C, 48.71; H, 2.48; N, 4.61; Rf=0.40 (hexane:ethyl acetate 2:1).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O-:10])=[O:9].Cl>N1C=CC=CC=1>[N+:8]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Valeryl chloride (12.06 g., 0.10 mole) is added dropwise to a cooled stirred solution of 4-nitroaniline (13.81 g., 0.10 mole) in pyridine (100 ml.). The resulting mixture is stirred at ambient temperature for one hour then heated (80°-100° C.) for twenty-four hours. The cooled solution is poured into cold 1 N hydrochloric acid (500ml.) with stirring. The precipitated solid is collected, washed with water and dried, 21.4 g., m.p. 107°-116° C. Recrystallization from butyl chloride provides material of m.p. 115°-118° C.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]([O:3][C@@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1ccccc1
Yield: 74.9 %

Procedure:
2.56 g (20.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 10.49 g (40.0 mmol) of triphenyl phosphine, and 4.88 g (40 mmol) of benzoic acid were added to 32 ml of dry THF, and a solution obtained by dissolving 6.97 g (40.0 mmol) of diethylazodicarboxylate in 32 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 23 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1 to 4:1). The purified residue was recrystallized from a solvent mixture of hexane and diethyl ether (a mixing ratio of 1:1) to obtain 3.48 g (yield: 74.9%) of 1,6-anhydro-3,4-dideoxy-2-O-(benzoyl)-β-D-erythro-hex-3-enopyranose.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4].O=[C:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[OH:4])[CH3:33])=[CH:27][CH:26]=1)=[O:30]
Reactant: NCC(O)c1cccc(Oc2ccccc2)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Oc3ccccc3)c2)cc1
Yield: 33.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-phenoxyphenyl)ethanol (prepared as described in Preparation 15), 3.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 3.7 g of sodium cyanoborohydride, 1.27 g of the title compound were obtained having an Rf=0.26 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36]O)[CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=2[N:4]=1.CS(Cl)(=O)=O.[CH3:48][NH:49][CH3:50]>>[F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:49]([CH3:50])[CH3:48])[CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[CH:41][C:5]=2[N:4]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCCO)c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: CS(=O)(=O)Cl
Product: CN(C)CCCN(c1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 95 %

Procedure:
Reaction of the above alcohol with methanesulfonyl chloride and aqueous dimethylamine as in Example 21 gave tert-butyl 4-{[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate in 95% yield: mp (CH2Cl2/hexanes) 190-191° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.41 and 8.35 (2d, J=7.6, 8.2 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 7.81 and 7.74 (2t, JHF=53.0, 52.9 Hz, 1H), 7.54-7.41 (m, 2H), 4.72-4.63 and 4.56-4.48 (2m, 1H), 4.14-4.07 (m, 2H), 3.83-3.78 (m, 4H), 3.70 (m, 4H), 3.56-3.45 (m, 2H), 2.82 (m, 2H), 2.29-2.25 (m, 2H), 2.14 and 2.12 (2s, 6H), 1.80-1.64 (m, 6H), 1.42 (s, 9H); Anal. Calcd. for C30H43F2N9O3: C, 58.5; H, 7.0; N, 20.5. Found: C, 58.35; H, 7.3; N, 20.3%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:12][CH:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[K+]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(N)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Product: CC(CNC(=O)OC(C)(C)C)Nc1ccc([N+](=O)[O-])c(N)n1

Procedure:
tert-Butyl {2-[(6-amino-5-nitropyridin-2-yl)amino]propyl}carbamate (Example 39A) is prepared in analogy to Example 38A from 2-amino-6-chloro-3-nitropyridine (637 mg, 3.7 mmol), tert-butyl (2-aminopropyl)carbamate (320 mg, 1.8 mmol) and potassium bicarbonate (368 mg, 3.7 mmol). 561 mg (98% of theory) of the product are obtained as a solid.