Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[N:26]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:30][C:27]4[CH:28]=[CH:29][O:25][N:26]=4)[CH2:21]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccon1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)C2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4(4-fluorophenyl)-1-pyrrolidin-3-yl-1H-imidazol-5-yl]pyrimidin-2-amine (C18) (300 mg, 0.925 mmol) and isoxazole-3-carbaldehyde (90 mg, 0.93 mmol) in toluene (5 mL) was added triethylamine (0.5 mL, 3.6 mmol), and the mixture was heated at 80° C. for 16 hours. After cooling to room temperature, the reaction was treated with sodium triacetoxyborohydride (500 mg, 2.36 mmol) and stirred for an additional 3 hours at 80° C. Solvents were removed in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by preparative thin layer chromatography on silica gel (Eluant: ethyl acetate) provided the product as a solid. Yield: 60 mg, 0.15 mmol, 16%. LCMS m/z 406.6 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.10 (m, 1H), 2.50-2.59 (m, 2H), 2.84 (dd, J=10.5, 6.7 Hz, 1H), 3.09 (dd, J=10.4, 2.4 Hz, 1H), 3.16 (m, 1H), 3.85 (AB quartet, JAB=14.0 Hz, ΔνAB=23.1 Hz, 2H), 5.29 (m, 1H), 6.40 (d, J=4.9 Hz, 1H), 6.55 (br s, 1H), 7.07 (dd, J=8.7, 8.7 Hz, 2H), 7.41 (dd, J=8.5, 5.5 Hz, 2H), 8.12 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 8.63 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[NH3:20].CO>>[NH2:20][CH2:14][C:12]([OH:13])([CH3:15])[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11]
Reactant: N
Reactant: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Solvent: CO
Product: CC(O)(CN)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.0 g, 3.48 mmoL) was dissolved in 7N NH3/MeOH solution (10 mL) at room temperature. The reaction mixture was stirred overnight and the solvent was removed to yield the title compound as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:3]([C:12]([Cl:17])=[O:14])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: O=C(Cl)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
89.3 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid (Example H3) are slowly heated to reflux temperature together with 60 ml of thionyl chloride and the mixture is then subsequently stirred at this temperature for 4 hours. Thereafter, it is cooled to 25° C. and concentrated to dryness in vacuo. Toluene is added twice more and the mixture is concentrated again to dryness. 94.0 g of the desired product are obtained as a yellow residue.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]1([CH2:42][OH:43])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([CH2:42][O:43][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCC1CCC1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OCC3CCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) was reacted with 2 equivalents each of n-butyl lithium and cyclobutylmethanol by the procedure described in Reference Examples 6 and 7 to afford 2-cyclobutylmethoxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=512 (M++1); Rt=4.40 min. 1H-NMR 400 MHz (CDCl3): δ 1.80-1.98 (m, 4H), 2.10-2.11(m, 2H), 2.74(m, 1H), 4.20 (d, J=7 Hz, 2H), 7.00 (m, 1H), 7.13-7.18 (m, 2H), 7.20-7.30 (m, 5H), 7.63-7.68 (m, 1H), 8.11 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:14])=[C:5]([C:10]([F:13])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:14][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([F:13])[CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1c(F)ccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a room temperature solution of methyl 3-(bromomethyl)-2,6-difluorobenzoate (14.24 g, nominally 51.2 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (9.1 g, 50.24 mmol, 1.0 equiv) in DMF (50 mL) was added K2CO3 (27.8 g, 201 mmol, 4.0 equiv) as a solid. The resulting mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with H2O. The combined aqueous layers were washed once with EtOAc, and the combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10%-60% EtOAc/hexanes) provided tert-butyl 4-(2,4-difluoro-3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (7.70 g, 41.4% over two steps). LCMS m/z (APCI)=371.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li]CCCC.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][N:17]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[O:21])=[CH:26][CH:27]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a solution of 1-bromo-2-methoxy-benzene (49.2 g, 0.263 mol) in dry THF (500 mL) was added dropwise n-BuLi (2.5 M in hexane, 105 mL, 0.263 mol) at −78° C. under N2 atmosphere. The mixture was stirred at this temperature for 1 hr and then a solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (50 g, 0.25 mol) in THF (100 mL) was added dropwise. The reaction mixture was warmed to room temperature, stirred overnight and then was quenched with a saturated solution of NH4Cl (300 mL). The separated aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over Na2SO4, evaporated in vacuo to give the crude product that was purified by column chromatography to yield (6-chloropyridin-3-yl)-(2-methoxyphenyl)-methanone as a white solid (31 g, 47.6%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9].N1C=CN=C1>CN(C=O)C.[Na+].[Cl-]>[Si:12]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of (R)-(+)-methyl lactate (2.95 g, 28.34 mmol) in DMF (20 mL) was added tert-butyldimethyl silyl chloride (6.41 g, 42.51 mmol) and imidazole (6.75 g, 99.18 mmol). After stirring at a room temperature for 18 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (90 mL) and extracted with petroleum ether (3×60 mL). The organic layer was washed with a cold 3% HCl solution (30 mL) and a saturated aqueous NaCl solution (30 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (105 g) with petroleum ether (300 mL), followed by 3% ethyl acetate in petroleum ether (600 mL). The 3% ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 5.26 g of (R)-(+)-Methyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (85% yield). 1H NMR (CDCl3): δ 4.26 (q, 1H, J=6.8 Hz, —CH), 3.65 (s, 3H, —OCH3), 1.32 (d, 3H, J=6.8 Hz, —CH3), 0.83 (s, 9H, Si—(CH3)3), 0.03 (s, 3H, Si—CH3), 0.00 (s, 3H, Si—CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(=O)C(F)(F)F)=[O:11])=[CH:5][C:4]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:25].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[O:11])=[CH:5][C:4]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:25]
Reactant: COc1ccc(NC(=O)[C@@H]2CCCN2C(=O)C(F)(F)F)cc1NC(=O)Nc1cnccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(NC(=O)[C@@H]2CCCN2)cc1NC(=O)Nc1cnccn1
Reaction time: 0.17 h

Procedure:
A suspension of (S)-1-(2,2,2-trifluoro-ethanoyl)-pyrrolidine-2-carboxylic acid [4-methoxy-3-(3-pyrazin-2-yl-ureido)-phenyl]-amide (Compound 36, Example 6) (22 mg, 0.05 mmol) in a mixture of methanol (MeOH, 5 mL) and water (about 0.25 mL) was treated with KOH (100 mg, large excess). Within 10 minutes, all ingredients were in solution. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried with sodium sulfate, and concentrated to a tan solid (13 mg, 75%). 1H NMR (300 MHz, d6-DMSO) δ: 10.13 (s, 1H), 10.03 (s, 1H), 9.85 (s, 1H), 8.90 (s, 1H), 8.38-8.28 (m, 2H), 8.25 (d, J=2.6 Hz, 1H), 7.41 (dd, J=8.8, 2.6 Hz), 6.98 (d, J=8.8 Hz, 1H), 3.88 (s, 3H, 3.69 (dd, J=8.7, 5.6 Hz, 1H), 2.94-2.87 (m, 2H), 2.10-1.97 (m, 1H), 1.81-1.60 (m, 3H). LRMS (ESI, positive) m/e 357.1 (M +1).
Reaction SMILES: [CH2:1](Cl)[CH3:2].[N:4]1([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([N:7]1[CH2:6][CH2:5][N:4]([CH2:10][CH2:11][CH2:12][O:13][C:14]([N:16]2[N:21]=[C:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:43])[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=3)[CH2:27][CH2:26][CH2:25]4)[CH:19]([CH3:44])[S:18][C:17]2=[O:45])=[O:15])[CH2:9][CH2:8]1)[CH3:2]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NN(C(=O)OCCCN5CCNCC5)C(=O)SC4C)ccc32)cc1OC
Reactant: CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1CCN(CCCOC(=O)N2N=C(c3ccc4c(c3)CCCN4C(=O)c3ccc(OC)c(OC)c3)C(C)SC2=O)CC1

Procedure:
1.3 g of ethyl chloride dissolved in 10 ml of toluene are added dropwise with stirring to a solution of 10 g of 3-(3-piperazinopropoxycarbonyl)-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 1.8 g of triethylamine in 100 ml of toluene, and the mixture is stirred with heating for one hour. The solvent is removed and the mixture is worked up in the conventional manner to give 3-[3-(1-ethyl-4-piperazinyl)-propoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH3:23])[CH2:17]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCCN(CC)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCCN(CC)C3)c2n1
Reaction time: 5 h

Procedure:
N2-Butyl-9-[(1-ethyl-3-piperidinyl)methyl]-8-methoxy-9H-purine-2,6-diamine (120 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 5 hours the reaction mixture was stripped, quenched with water then made basic with 1M aq potassium carbonate. The resulting solid was filtered, washed and dried to give the title compound as a crystalline solid, yield 86 mg.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH:11]=1>ClCCCl>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:11]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Solvent: ClCCCl
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Br)c(N)c2F)c1F
Temperature: 23 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
N-Bromosuccinimide (NBS; 580 mg, 3.3 mmol, 1.1 equiv) was added to a stirred suspension of benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (1.2 g, 3.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) at 23° C. The resulting bright yellow mixture was stirred at 23° C. for 72 h. The brown reaction mixture was concentrated by N2 stream and the residue was purified by silica gel column chromatography (eluting with 29% EtOAc/hexane) to afford the desired product, benzyl 4-amino-3-bromo-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a tan powder (1.3 g, 93%): mp 144-146° C.; IR (thin film) 3370 (s), 3225 (w), 3190 (w), 3093 (w), 3066 (w), 3037 (w), 2948 (w), 1731 (s), 1616 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.41-7.33 (m, 3H), 7.26-7.22 (m, 2H), 5.42 (s, 2H), 4.98 (br s, 2H), 3.96 (d, J=1 Hz, 3H); ESIMS m/z 485 ([M+H]+).
Reaction SMILES: [OH-:1].[K+].C1(C)C=CC=CC=1.[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:21]#[N:22])=[N:18][O:19][CH3:20].Cl>O>[CH3:10][C:11]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:12]=1[O:13][CH2:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](=[N:18][O:19][CH3:20])[C:21]([NH2:22])=[O:1]
Reactant: [OH-]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
85% Potassium hydroxide (0.40 g, 6.0 mmol) and toluene (5 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminobenzyl cyanide (E/Z=15/85)(1.47 g, 5.0 mmol). The mixture was stirred at 95° C. for 2 hours. After completion of the reaction, water was added. The mixture was neutralized with conc. hydrochloric acid, extracted with toluene (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.30 g, Yield: 83.2%, E/Z=15/85).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc2oc(-c3ccc(O)c(Cl)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 254-256° C.; MS m/e 260 (M−H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3Br)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38]1([C:44]#[CH:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[C:45]#[C:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(C#Cc4ccccc4)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 75 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-bromo-9H-purin-9-yl)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (1.26 g, 2.67 mmol), CuI (0.102 g, 0.534 mmol), and Pd(PPh3)2Cl2 (0.187 g, 0.267 mmol) in DMF was added DIPEA (0.930 mL, 5.34 mmol) and phenylacetylene (1.17 mL, 10.69 mmol). The mixture was stirred at 75° C. for 1 hour then concentrated. The residue was dissolved in CH2Cl2 (70 mL) and washed with saturated aq EDTA.Na2 (3×50 mL). The combined organics were dried (Na2SO4) and concentrated. The dark crude oil was purified by flash chromatography (40% EtOAc/hexanes) to afford the title compound (1.2 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12](OCC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:6](=[O:11])[CH2:5]2
Reactant: CCOC(OCC)OCC
Reactant: O=C1Cc2cc(F)ccc2N1
Product: CCOC(OCC)N1C(=O)Cc2cc(F)ccc21
Yield: 40 %

Procedure:
A solution of 5-fluorooxindole (980 mg, 6.5 mmol), (prepared according to Synthesis 1993, 51), in triethyl orthoformate (25 ml) was stirred and heated at reflux for 8 hours. The volatiles were removed by evaporation and the crude product purified by flash chromatography using petroleum ether/ether 7/3 as eluent to give 5-fluoro-1-diethoxymethyloxindole (637 mg, 40%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[NH2:15][CH2:16][CH:17]1[CH2:19][CH2:18]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:15][CH2:16][CH:17]2[CH2:19][CH2:18]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with aminomethyl-cyclopropane in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-(cyclo-propylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=268.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:3]=1>C(O)(=O)C.O.[Zn]>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2cn1
Yield: 39.8 %

Procedure:
Zinc powder (0.63 g) was added portionwise to a solution of 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.82 g) in a mixture of acetic acid (135 ml) and water (15 ml). On completion of the addition the mixture was heated under reflux for a period of 1 hour and was then filtered to remove any residual zinc. The solvent was removed by distillation under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(7-chloroisoquinolin-3-yl)-N-methylamino]phenol (1.0 g) as an orange solid mp 140° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:25]12[O:30][CH:29]1[CH2:28][O:27][CH2:26]2.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[F:1][C:2]1[C:3]([O:24][C@H:29]2[C@H:25]([OH:30])[CH2:26][O:27][CH2:28]2)=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Reactant: C1OCC2OC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1COC[C@H]1O)C(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 21.2 %

Procedure:
27B (680 mg, 2.034 mmol) was mixed with 3,6-dioxabicyclo[3.1.0]hexane (876 mg, 10.17 mmol), and K2CO3 (1546 mg, 11.19 mmol) in acetonitrile (1 mL) and H2O (1 mL) in a sealed tube. The mixture was stirred at 100° C. for 20 h. The reaction was quenched with H2O then extracted with EtOAc (2×) and concentrated. The residue was purified by flash column chromatography (0-90% EtOAc/hexanes) to give a mixture of diastereomers as yellow oil. The diastereomers were further separated by a prep chiral HPLC equipped with a OJ Column to give the first peak 27C (181 mg, 0.431 mmol, 21.17% yield). The relative stereochemistry of hydroxyether is trans however absolute stereochemistry is undetermined MS (ESI) m/z: 421.2 (M+H)+.