Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].Cl[C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:4]2[N:3]=[C:2]([NH2:1])[N:6]([C:7](=[O:16])[C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:5]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])=[O:43])[CH3:42]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)NS(=O)(=O)c1ccc(Nc2nc(N)n(C(=O)c3c(F)cccc3F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (1.0 g, 2.5 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (2.8 mL, 1.0 M solu THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then ethyl 4-chloro-4-oxobutyrate (0.46 g in 10 mL THF, 2.8 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. After being concentrated, the residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/9:1) to afford the desired product (200 mg, 15%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.72 (d, 2H), 7.70 (m, 1H), 7.50 (d, 2H), 7.15 (t, 2 H), 4.20 (q, 2H), 3.32 (s, 2H), 2.71 (s, 2H), 1.25 (t, 2H); MS (ESI) m/z: 523 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Clc1cnccn1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cnccn1
Reaction time: 0.08 h

Procedure:
A solution of 2-dimethylaminoethanol (1 mL) in THF (20 mL) was treated with potassium tert-butoxide (1.2 g). After 5 min, chloropyrazine (2 g) was added and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold water, the mixture acidified, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 10%-EtOH-1%-NH4OH-CHCl3 to give 2-(2-dimethylaminoethoxy)pyrazine (1.3 g). The HCl salt crystallized from 2-propanol as a white solid, m.p. 151-153° C. (Compound 26).
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2O)[CH2:3]1.[CH3:23][O:24][C:25](Cl)=[O:26]>N1C=CC=CC=1>[C:25]([C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:25]([O:24][CH3:23])=[O:26])[CH2:3]1)([O:24][CH3:23])=[O:26]
Reactant: COC(=O)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(=O)OC)[C@@]4(C)CC[C@@H]32)C1
Yield: 81 %

Procedure:
Prepared from 3β,17β-dihydroxyandrost-5-ene-7-one and methylchloroformate in pyridine at 0-5° C. Yield 81%, m.p. 167-9° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH:16]1([NH:22][C:13]([C:10]2[N:11]=[CH:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ncn(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ncn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid (1.54 g, 7.6 mmol), cyclohexylamine (0.87 mL, 7.6 mmol) and N,N-diisopropylethylamine (2.65 mL, 15.1 mmol) in DMF (30 mL) was added HBTU (3.45 g, 9.1 mmol). The solution was then stirred at room temperature overnight. Aqueous hydrochloric acid was added and the solution was filtered to yield 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid cyclohexylamide as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:20])([Cl:19])[CH:12]([NH2:18])[NH:13][C:14](=[O:17])[CH2:15][Cl:16].C(N(CC)CC)C>CC(C)=O>[Cl:10][C:11]([Cl:19])([Cl:20])[CH:12]([NH:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:13][C:14](=[O:17])[CH2:15][Cl:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(NC(=O)CCl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
Benzoyl chloride (4.7g) in acetone (5ml) was added dropwise to a solution of 1,1,1-trichloro-2-amino-2-(chloroacetamido)ethane (8g) in acetone (50ml) containing triethylamine (3.4g). The temperature rose to 50°. The mixture was stirred for 2 hours. The salt was filtered off and the filtrate poured into water. The solid formed was collected, washed with water and dried (10g). Recrystallisation from nitromethane gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (8.7g. m.p. 211°-213°).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:15].CO>CO>[CH3:14][O:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][NH:15][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: N
Reactant: COC(=O)c1cc(OC)ccc1CBr
Solvent: CO
Product: COc1ccc2c(c1)C(=O)NC2
Temperature: 125 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution of methyl 2-(bromomethyl)-5-methoxybenzoate ((75), 5.0 g, 19.3 mmol) in MeOH was placed in pressure flask and to it ammonia/methanol (2M, 30 ml) was added. Resulting mixture was stirred at 125° C. for 2 hr. The solvent and excess NH3 was removed in vacuo and the residue was triturated with Hexane/EtOAc (1:2 ratio). The compound was filtrated under vacuum and air-dried for 2 hr to give the title compound (2.51 g, 65%) as a pale yellow solid. The filtrated was concentrated and purified on silica gel (Hexane/EtOAc/MeOH 3:1:0.5 ratio) to yield another 270 mg of desired compound. Combined yield was 86%. MS (ES) m/z 164.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(O)Cc1ccccc1Nc1cc(Cl)cc(Cl)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 3,5-dichloroaniline to yield 2-[(3,5-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[C:2]([NH:22][NH2:23])[N:3]=[N:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: Clc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
3-Chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazine (5.1 g, 16.9 mmol) was dissolved in pyridine (20 mL) and hydrazine mono-hydrate (17.0 mL, 350.5 mmol) was added. The reaction mixture was stirred at reflux for 40 min. After this time, the reaction mixture was cooled to RT and then concentrated to half of the original volume under reduced pressure. The resultant mixture was diluted with water (100 mL). The yellow colored solid was collected by filtration and rinsed thoroughly with water. The solid was dried in a vacuum oven at 40° C. to give the title compound, 1-(5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-yl)hydrazine, (4.4 g, 88%) as a yellow powder. HPLC: 1.01 min; MS, M+H=298.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:34])([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=1.C1C(=O)N([Br:42])C(=O)C1>>[Br:42][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:34])([CH3:33])[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)cc1
Yield: 48.3 %

Procedure:
Following General Procedure I, tert-butyl 2-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-2-methylpropylcarbamate (600 mg, 1.3 mmol) was reacted with NBS (330 mg, 1.9 mmol) to afford the desired product (350 mg, 51%) as a yellow solid: ESI MS m/z 557 [C27H29BrN2O4S+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].[CH3:12][Si:13]([CH2:16][CH2:17][O:18][CH2:19]Cl)([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][Si:13]([CH3:15])([CH3:14])[CH2:16][CH2:17][O:18][CH2:19][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: c1cnc2[nH]ncc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1H-pyrazolo[3,4-b]pyridine (380 mg, 3.2 mmol) in DMF (5 mL) was added NaH (60% dispersion in mineral oil, 153 mg, 3.8 mmol). After stirring for 20 min, the mixture was heated with a heat gun and then allowed to cool to rt. SEM-Cl (647 μL, 3.8 mmol) was added dropwise and stirring continued for 2 h. The resulting mixture was partitioned between water and ethyl acetate. The organic layer was separated and concentrated, and the residue was purified by flash column chromatography (silica gel, eluting with 0-50% ethyl acetate in hexanes) to provide 1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, which was dissolved in ethanol (30 mL) and flushed with a nitrogen stream. Palladium on charcoal (5% wet on carbon, ˜50 mg) was added and the mixture was placed under hydrogen (50 psi) for 2 days. The reaction mixture was filtered, and the filtrate was concentrated to provide the title compound: 1H NMR (500 MHz, CDCl3) δ 7.13 (s, 1H), 5.24 (s, 2H), 3.68 (br, 1H), 3.54 (t, J=8.2 Hz, 2H), 3.28 (m, 2H), 2.51 (t, J=6.1, 2H), 1.81 (m, 2H), 0.89 (t, J=8.2 Hz, 2H), −0.01 (s, 9H).
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:17][CH2:18][CH2:19]Cl>>[C:1]1([C:7]2[O:8][CH2:17][CH2:18][CH2:19][C:9]=2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: ClCCCBr
Product: c1ccc(C2=C(c3ccccc3)OCCC2)cc1

Procedure:
In the first stage 19.6 g of desoxybenzoin is alkylated with 15.8 g of 3-bromo-1-chloropropane according to the procedure described in method 1 except that the reaction is carried out at room temperature. Isolation gives an intermediate, 2,3-diphenyl-4,5-dihydro-6H-pyran in quantitative yield, but the product contains about 10% of noncyclic O-alkylation product. The m.p. of a sample which has been chromatographically purified and recrystallized from methanol is 119°-22° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[NH:21][C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][Si:38]([CH3:45])([CH3:44])[CH2:39][CH2:40][O:41][CH2:42]Cl>CN(C=O)C.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:21]([CH2:42][O:41][CH2:40][CH2:39][Si:38]([CH3:45])([CH3:44])[CH3:37])[C:20]3[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[N:16][C:15]=3[N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)[nH]c2c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(N2CCCC2)nc2nc(-c3cnn(Cc4ccccc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
A mixture of 8-(1-Benzyl-1H-pyrazol-4-yl)-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one (0.83 g, 2.1 mmol) and potassium carbonate (0.857 g, 6.2 mmol) was taken in DMF (5 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.0 ml, 6.2 mmol) was added drop wise at 0° C. and the mixture was stirred at 20° C. for 4 hours. The mixture was cooled to 10° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (3×15 ml). The organic layer was washed with saturated brine solution (2×15 ml) and dried over Na2SO4. Solvent was evaporated and the residue was further purified by column chromatography to obtain the above product as pale yellow semisolid (0.325 g, 30%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1ccccc1CBr
Product: COc1ccc(CN(Cc2ccccc2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 1-(bromomethyl)-2-fluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.29 (s, 2H), 4.37 (s, 2H), 6.72 (d, 2H, J=8 Hz), 7.01-7.03 (m, 6H), 7.93 (d, 2H, J=8 Hz), 8.08 (d, 2H, J=8 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CCOCC>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2([OH:22])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)nc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC1(c2ccc(Cl)nc2)CCNCC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
HCl (4M in dioxan, 4.22 mL, 16.88 mmol) was added in one portion to a stirred suspension of tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (1.32 g, 4.22 mmol) in ethyl acetate (20 mL) at ambient temperature. The resulting mixture was stirred at 50° C. for 90 minutes then cooled to room temperature, diluted with ether (20 mL) and filtered. The filtered solid was washed with ether and dried then taken up in methanol, applied to an SCX column and eluted with methanol followed by 2M ammonia in methanol. Product-containing fractions were combined and evaporated then purified by flash silica chromatography, elution gradient 10 to 20% 2M ammonia in methanol in DCM. Pure fractions were evaporated to dryness to afford 4-(6-chloropyridin-3-yl)piperidin-4-ol (0.43 g, 48%) as a pale orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].[CH3:22][O:23][C:24](=[O:35])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](OC)[CH:28]=1>>[NH2:12][C:11]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:2]=2[N:1]=[C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[C:24]([O:23][CH3:22])=[O:35]
Reactant: COC(=O)C=Cc1cccc(OC)c1
Reactant: COc1ccc(Cn2c(N)c(C#N)c3c2CCCC3)cc1
Product: COC(=O)c1c(-c2ccccc2)nc2c(c1N)c1c(n2Cc2ccc(OC)cc2)CCCC1
Yield: 73 %

Procedure:
Using a procedure similar to Description 6, the title compound (D12) was prepared in 73% yield from 2-amino-3-cyano-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydroindole (D5) and methyl-3-methoxycinnamate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH3:13])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=3)[CH3:13])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(c1ccc(O)cc1)c1ncnc2cc(Cl)ccc12
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2ncnc3cc(Cl)ccc23)cc1

Procedure:
4-[N-(7-Chloro-4-quinazolinyl)-N-methylamino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 3 part(b), to give ethyl 2-{4-[N-(7-chloro-4-quinazolinyl)-N-methylamino]phenoxy}propionate as a yellow solid mp 92° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:21][CH2:20][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCc2ccccc2)c(C=O)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 26.9 g (125 mmol) (2-Bromo-ethoxymethyl)-benzene (Adrich) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 6 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulphate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate:hexane 1:3→1:2). The desired product 2a was obtained in 86% yield (24.6 g, 86 mmol) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Fc1ccc([S-])c(F)c1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#Cc1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (6.1 g) in methanol (30 ml) was added dropwise to a solution of 3-chloro-4-nitrobenzonitrile (5 g) in toluene (50 ml). The mixture was stirred for 5 hours at room temperature, washed with water, and concentrated to dryness. The oily residue was crystallized from a mixture of ethanol and hexane to give crystals of 3-(2,4-difluorophenylthio)-4-nitrobenzonitrile (3.6 g).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[C:7]([O:19][CH2:20][CH3:21])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18]1)[CH3:21]
Reactant: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminum hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h, the excess of hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL), and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]2[C@H:12]([N:20]([CH3:30])[C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixed solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloropyrimidin-4-amine (405 mg, 0.98 mmol) in THF (10.0 mL) and DMF (2.50 mL) was added sodium hydride (47.0 mg, 1.17 mmol) under an atmosphere of Argon, and the mixture was stirred for 15 minutes. Methyl iodide (0.08 mL, 1.27 mmol) was added to the mixture, and the resulting mixture was stirred for 1 h. After quenching by addition of brine (20.0 mL), the mixture was extracted with ethyl acetate (3×40.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 15% ethyl acetate in DCM to afford the title compound (381 mg, 91%) as a colorless oil. LC/MS: Rt=2.55 min, ES+ 428.3 (AA standard).
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1.[H-].[Na+].[CH3:11]I>O1CCCC1>[Br:1][CH2:2][C:3]1([CH2:7][O:8][CH3:11])[CH2:6][O:5][CH2:4]1
Reactant: OCC1(CBr)COC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(CBr)COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To a stirring solution of (3-Bromomethyl-oxetan-3-yl)-methanol (200 mg, 1.104 mmol) in tetrahydrofuran (15 mL) at 0° C., was added sodium hydride (63 mg, 2.65 mmol) and stirred for 15 min. To this methyl iodide (629 mg, 4.419 mmol) was added to the above reaction mixture and the resultant reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 3-(bromomethyl)-3-(methoxymethyl)oxetane as a liquid (120 mg, 55%).