Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][CH:24]=1>>[CH3:29][C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[N:12][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][C:26]=1[CH:30]([OH:35])[C:31]([F:34])([F:32])[F:33]
Reactant: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1N
Reactant: Cc1nc(Cl)ccc1C(O)C(F)(F)F
Product: Cc1nc(Nc2sc(-c3ccc(N4CCOCC4)nc3)cc2C(N)=O)ccc1C(O)C(F)(F)F

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-(6-morpholin-4-ylpyridin-3-yl)thiophene-3-carboxamide (150 mg, 0.49 mmol) and 1-(6-chloro-2-methylpyridin-3-yl)-2,2,2-trifluoroethanol (111 mg, 0.49 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccc(F)cc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(4-fluoro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[N:5]1([C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[O:12][CH2:13][CH:14]2[O:16][CH2:15]2)[CH:9]=[CH:8][CH:7]=[CH:6]1>C(O)(C)C>[CH:1]([NH:4][CH2:15][CH:14]([OH:16])[CH2:13][O:12][C:11]1[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=1[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: c1ccc(-n2cccc2)c(OCC2CO2)c1
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccccc1-n1cccc1

Procedure:
50 ml of isopropylamine are added to a solution of 26.9 g of 1-[o-(pyrrol-1-yl)-phenoxy]-2,3-epoxy-propane in 250 ml of isopropanol and the mixture is heated to the boil under reflux for 1 1/2 hours. The oil which remains after evaporating off the volatile constituents in vacuo is distilled in a bulb tube under a high vacuum and gives 1-iso-propylamino-3[o-(pyrrol-1-yl)-phenoxy]-2-propanol as a colourless oil of boiling point 125°-135° C/0.04 mm Hg. The distillate which crystallises can be recrystallised from ether/petroleum ether and gives crystals of melting point 80°-81° C and is in every respect identical with the product obtained in Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][S:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31]>C(O)(=O)C.N#N.CCOC(C)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:17](=[O:26])[C:16]3[C:11](=[CH:12][C:13]([C:27](=[N:30][OH:31])[NH2:28])=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NO
Agent: N#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1

Procedure:
A solution of tert-butyl-2-(7-cyano-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10A, 0.05 g, 0.12 mmol) in 50% NH2OH aqueous solution (3 mL) and 20 μL acetic acid was microwaved under high absorption in N2 atmosphere 105° C. for 40 minutes. The reaction was diluted with EtOAc and washed with water. The organic was concentrated to yield tert-butyl 2-(3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10B), MS (M+H)=445.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=1[O:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=3[O:29][C:30]3[N:31]=[CH:32][CH:33]=[CH:34][N:35]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1Oc1ncccn1
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccccc2Oc2ncccn2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-(2-bromophenoxy)pyrimidine. MS (ESI): mass calcd. for C21H13FN6O, 384.11; m/z found, 385.0 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.55 (d, J=4.8, 2H), 8.20 (s, 1H), 7.61 (dd, J=7.7, 1.7, 1H), 7.57-7.49 (m, 2H), 7.44-7.37 (m, 3H), 7.35 (s, 2H), 7.32 (dd, J=8.1, 1.2, 1H), 7.19-7.15 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1COCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([C:17]3([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]3)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2ccoc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3cccc(F)c3o2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To a solution of 7-fluorobenzofuran (0.3 g, 1.807 mmol) in dry THF (4.8 mL) at −78° C. under an argon atmosphere was slowly added BuLi (1.3 mL, 2.078 mmol). Upon completion of addition, the mixture was stirred at −78° C. for 20 min. After this time, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.36 g, 1.807 mmol) in THF (2.4 mL) was slowly added. The reaction mixture was warmed to −40° C., where it stirred for 2 hrs. At the conclusion of this period, the reaction mixture was quenched with aqueous NH4Cl (saturated, 5 mL) and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with H2O (2×4 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 1D as a white solid (530 mg, 94.7% purity, 83% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]C(=O)C)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][SH:10])=[CH:4][CH:3]=1
Reactant: CC(=O)SCCc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(CCS)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thioacetic acid S-[2-(4-fluoro-phenyl)-ethyl]ester (9.9 g, 50 mmol) was dissolved in anhydrous THF (300 mL) and LiAlH4 (7.5 g, 200 mmol) was added in several small portions. After the addition was completed the mixture was stirred for 2 h at room temperature then cooled down to 0° C. and excess LiAlH4 was hydrolyzed by the addition of H2O (10 mL) and aq. HCl (2N, 200 mL). The resulting clear solution was extracted with EtOAc (3×200 mL) and the combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The unpleasant smelling crude product (8.17 g, 104%) was carried on into the next step as obtained. 1H NMR (400 MHz, CDCl3): δ 7.17 (dd, 2H), 7.02 (t, 2H), 2.89 (t, 2H), 2.78 (dd, 2H), 1.38 (t, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4].[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:29])([F:28])[CH2:25][CH:24]1[C:30]([OH:32])=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].CCN(CC)CC>CC#N>[C:16]([O:20][C:21]([N:23]1[CH2:27][C:26]([F:28])([F:29])[CH2:25][CH:24]1[C:30]([O:32][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[CH:6]=1)=[O:4])=[O:31])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(CBr)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)OCC(=O)c1ccc2cc(Br)ccc2c1
Yield: 83 %

Procedure:
2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone (1 g, 3.07 mmol) and 4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (849 mg, 3.38 mmol) were suspended in MeCN (15 mL) and treated with Et3N (0.45 mL, 3.22 mmol). After stirring o/n, the reaction mixture was concentrated. The resulting residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (0% to 20% EtOAc/Hex) to provide the title compound (1.27 g, 83%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.I[CH3:17]>O1CCCC1>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][O:15][CH3:17])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CI
Reactant: COc1cccc2cc(CO)oc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc2cccc(OC)c2o1
Reaction time: 8 h

Procedure:
Sodium hydride (3.82 g, 60% in mineral oil) was added to a solution of 7-methoxy-benzofuran-2-ylmethanol (11.21 g) in dry tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen at room temperature. After 10 minutes iodomethane (15.67 ml) was added and the reaction was left to stir overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic extract was washed with water (50 ml), followed by brine (50 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (13.32 g) as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][S:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]#[N:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1COCC1>[CH:14]1([CH2:17][C:9]2([C:12]#[N:13])[CH2:10][CH2:11][CH:6]([S:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:7][CH2:8]2)[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: N#CC1CCC(SCC2CC2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(CC2CC2)CCC(SCC2CC2)CC1

Procedure:
4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (either isomer) (1.95 g; 10 mmol) was dissolved in THF (10 mL) and cyclopropyl methyl bromide (2.7 g; 20 mmol) was added followed by the dropwise addition of sodium hexamethyldisilazide (2M, 10 mL, 20 mmol). The reaction was stirred for half an hour and then was quenched with brine and extracted into ethyl acetate. The organic layer was dried and product was purified rigorously from its less polar isomer on silica using a Biotage 65i cartridge eluting with EtOAc/isohexane to yield 1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile as an oil. (2 g, 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([O:17]CC)=O)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(CC)c1=O

Procedure:
Reagents: Comp 40 (0.5 mmols, 0.15 g); octanoyl hydrazine (0.55 mmols, 0.09 g). Yield: 0.06 g (29%), white solid, m.p.=161° C.-162° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.Cl.[CH3:21][NH:22][CH3:23].C(Cl)CCl.Cl>C1COCC1.CC(O)C.CN(C1C=CN=CC=1)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([N:22]([CH3:23])[CH3:21])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CN(C)C(=O)c1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To a solution of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (2.5 g, 6.72 mmol) and N,N-dimethylamine hydrochloride (0.8 g, 10.08 mmol) in THF:IPA (7:3) (25 mL) was added EDC. HCl (1.5 g, 8.06 mmol) followed by DMAP (341 mg, 2.80 mmol) in one lot at RT. The reaction was stirred at RT for 12 h, diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic layer was separated and dried over Na2SO4, filtered and concentrated to give 3-iodo-N,N-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxamide (2.0 g, 75%) as an off white solid. MS (ESI, pos. ion) m/z: 400.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, 1 H, J=8.7 Hz), 7.56 (dd, 1 H, J=8.7, 1.3 Hz), 7.48 (s, 1H), 5.91 (dd, 1 H, J=9.7, 2.0 Hz), 3.89 (d, 1 H, J=11.3 Hz), 3.72-3.78 (m, 1H), 2.99 (s, 6H), 2.37 (dd, 1 H, J=12.4, 9.6 Hz), 1.97-2.04 (m, 2H), 1.72-1.77 (m, 1H), 1.59 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[CH:35]1([C:33]([NH:32][C:28]2[CH:27]=[C:26]([CH:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]4([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:15])[CH2:25][CH2:24]3)[CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1)C1CC1

Procedure:
Example 121 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.94–7.72 (br, 1H), 7.48–6.84 (m, 7H), 6.75 (d, 1H, J=7.2 Hz), 6.68–6.55 (br, 1H), 3.25–3.05 (m, 4H), 2.58–2.39 (m, 3H), 2.33–2.15 (m, 2H), 2.00–1.48 (m, 15H), 1.13–1.01 (m, 2H), 0.93–0.73 (m, 2H); ESMS m/e: 492.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:20].[C:21]1([CH2:27][C:28](=[NH:32])OCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[ClH:20].[F:18][C:16]([F:17])([F:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:28](=[NH:32])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccccc1C(F)(F)F
Yield: 4.9 %

Procedure:
A mixture of 2-amino-3-(2-trifluoromethylbenzyloxy)pyridine (5.36 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) and recrystallisation from ethanol/ether to obtain the product (0.41 g), m.p. 105°-112° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)(=[O:18])=[O:17])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N:21]1[CH:20]=[C:19]([S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][OH:8])(=[O:17])=[O:18])[CH:24]=[N:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1S(=O)(=O)c1cncnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cncnc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-[2-(tert-butyl-dimethylsilanyloxymethyl)benzenesulfonyl]pyrimidine (2.1 g) and tetrahydrofuran (2.0 mL) was treated with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (7.5 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound a pale brown solid (0.64 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH2:29][OH:30])[C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:31]([OH:34])([CH3:33])[CH3:32])=[C:27]([CH2:29][OH:30])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1ccc(Cl)nc1CO
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C(C)(C)O)c(CO)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (105 mg, 0.34 mmol) and 2-[6-chloro-2-(hydroxymethyl)pyridin-3-yl]propan-2-ol (71 mg, 0.35 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20](OC)=[O:21].CC(C)([O-])C.[K+]>COC(C)(C)C>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][OH:21]
Reactant: COC(=O)Cc1cc(Cl)ccc1Oc1ccccc1
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (5-chloro-2-phenoxy-phenyl)-acetic acid methyl ester (167 g, 605 mmol) and methyl formate (173 mL, 2.8 mol) in t-butyl methyl ether (1 L) was cooled to −10° C. To this solution was added potassium t-butoxide (115 g, 1.03 mol) portionwise so that the temperature remained below 0° C. After 30 minutes, the reaction was quenched by addition of 4N aqueous hydrochloric acid (400 mL). The organic layer was separated and washed with water (3×350 mL) and saturated brine (350 mL). The organic fractions were combined and concentrated to dryness and used without purification. The product is 90% E as shown by NMR. 1H NMR (400 MHz, CDCl3) 3.6 (s, 3H, E methyl group; Z methyl is at 3.7), 6.8 (d, 1H), 6.9 (m, 2H), 7.0 (t, 1H), 7.2 (m, 3H), 7.3 (m, 2H), 11.8 (d, 1H, E hydroxy proton; Z hydroxy proton is at 4.7).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]#[CH:9])[CH:5]=[C:4]([C:10](OCC)=[O:11])[S:3]1.B(F)(F)F.CCOCC.[H-].C([Al+]CC(C)C)C(C)C.[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:7]([N:6]1[CH:5]=[C:4]([CH2:10][OH:11])[S:3][C:2]1=[O:1])[C:8]#[CH:9]
Reactant: C#CCn1cc(C(=O)OCC)sc1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: FB(F)F
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#CCn1cc(CO)sc1=O
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A solution of 8.44 g of the product of Step B in 100 ml of toluene was cooled to -65° C. to -70° C. and 5.6 g of boron trifluoride etherate were added. The mixture was stirred for 30 minutes and 200 ml of a 1.2M solution of diisobutyl aluminium hydride in toluene were introduced over 2 hours 15 minutes. Stirring was carried out for a further 30 minutes and the mixture was poured into 1.5 l of a M solution of potassium and sodium tartrate. After stirring for one hour and decanting, extraction was carried out with ethyl acetate. The extracts were washed with water saturated with sodium chloride, dried and brought to dryness. The residue was chromatographed and elution with a hexane-chloroform-acetone mixture (6-2-2) yielded. 2.33 g of the expected product melting at 97° to 98° C.
Reaction SMILES: C(O[CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:9]=[CH:8][N:7]=1)(=O)C.S(Cl)(Cl)=O.[SH:22][C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C[O-].[Na+]>C(Cl)(Cl)Cl.CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[C:11]=1[CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1ccnc(COC(C)=O)c1C
Reactant: Sc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 106.5 %

Procedure:
8.3 g of 2-acetoxymethyl-3-methyl-4-butoxy-pyridine was dissolved in chloroform, and 21.6 g (4 eq.) of thionyl chloride was added. The mixture was heated to reflux for one hour and then concentrated, and a residue resulting therefrom was dissolved in methanol. The solution was added in advance to 6.1 g (1 eq.) of 2-mercaptobenzimidazole, 230 mL of a 28% sodium methoxide solution, and 120 mL of methanol, and the mixture was heated to reflux for one hour. Methanol was distilled off, ice was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate. Subsequently, the ethyl acetate solution was concentrated to dryness, and the resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 12.2 g of yellow crystals. 12.2 g of the crystals were recrystallized from ethyl acetate/1-hexane, to obtain 4.2 g of colorless crystals. Total yield 10.8% (purity by HPLC: 97.0%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19](O)[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:24])[N:12]=1)[CH3:2].O=S(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][CH:19]([C:14]1[C:15]([O:17][CH3:18])=[N:16][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[N:12][C:13]=1[CH3:24])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(O)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCC(Cl)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan-1-ol (1 g, 3 mmol) [prepared as described in Example 10] in dry DCM (20 mL) is added SOCl2 (7 mL 0.015 mol) dropwise under nitrogen. The solution is then allowed to stir at room temperature for 1 h. The reaction mixture is concentrated and azeotroped with toluene twice to obtain 5-(1-chloro-butyl)-2-(2,6-diethyl-phenyl)-4-methoxy-6-methyl-pyrimidine which is used in standard nucleophilic displacement reactions to obtain a variety of compounds including the following:
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6]([CH3:18])([CH3:17])[C:7](=[O:16])[NH:8][C:9]2=[O:15])=[CH:4][C:3]=1[Br:19]>CC(O)=O.[Fe]>[NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:17])([CH3:18])[C:7](=[O:16])[NH:8][C:9]2=[O:15])=[CH:4][C:3]=1[Br:19]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2N
Temperature: 70 °C
Yield: 105.7 %

Procedure:
A mixture of 7-amino-6-bromo-4,4-dimethyl-8-nitroisoquinoline-1,3(2H,4H)-dione (2 g, 6.09 mmol) and iron powder (325 mesh, 2.38 g, 42.67 mmol) in AcOH (40 mL) was heated to 70° C. for 8 h. The excess iron was removed using a magnetic bar and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, and successively washed with water, aqueous saturated NaHCO3, and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound (1.92 g, 100% yield).