Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([OH:28])=[C:26]([CH3:27])[C:13]2=3)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl.Cl[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([O:28][CH2:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[C:26]([CH3:27])[C:13]2=3)=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccncc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 187.3 mg, 4.98 mmol) was added to a solution of 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (817.7 mg, 2.15 mmol) in N,N-dimethylformamide (30 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-chloromethylpyridine hydrochloride (364.5 mg, 2.22 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=4/1) to obtain the title compound (575 mg, yield 57%).
Reaction SMILES: COC(=O)CC1C=CC(O)=C(Cl)C=1.C(=O)([O-])[O-].[K+].[K+].C1(CC2C3ON=C(C4C=CC=CC=4)C=3C=CC=2OCCCBr)CC1.C[CH:45]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH2:57][CH:58]([O:60][C:61]2[CH:62]=[CH:63][C:64]3[C:65]([C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)=[N:66][O:67][C:68]=3[C:69]=2[CH2:70][CH:71]2[CH2:73][CH2:72]2)[CH3:59])=[C:51]([Cl:80])[CH:50]=1)[C:46]([OH:48])=[O:47].[OH-].[Li+]>CN(C=O)C.CO.O>[Cl:80][C:51]1[CH:50]=[C:49]([CH2:45][C:46]([OH:48])=[O:47])[CH:54]=[CH:53][C:52]=1[O:55][CH2:56][CH2:57][CH:58]([O:60][C:61]1[CH:62]=[CH:63][C:64]2[C:65]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)=[N:66][O:67][C:68]=2[C:69]=1[CH2:70][CH:71]1[CH2:73][CH2:72]1)[CH3:59]
Reactant: CC(CCOc1ccc(C(C)C(=O)O)cc1Cl)Oc1ccc2c(-c3ccccc3)noc2c1CC1CC1
Agent: BrCCCOc1ccc2c(-c3ccccc3)noc2c1CC1CC1
Agent: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(CCOc1ccc(CC(=O)O)cc1Cl)Oc1ccc2c(-c3ccccc3)noc2c1CC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-cyclopropylmethyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole (0.25 grams) in 2-butanone (3.0 mL) was treated with 1,3-dibromopropane (0.48 mL) and potassium carbonate (0.50 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole. A solution of 3-chloro-4-hydroxyphenylacetic acid methyl ester (42.0 mg) in DMF (1.0 mL) was treated with potassium carbonate (26 mg) and this mixture was stirred for 0.5 hours. Then 7-cyclopropylmethyl-3-phenyl-6-(3-bromopropyloxy)benz-[4,5]-isoxazole was added and the mixture was stirred over night. The reaction mixture was partitioned between ethyl acetate and 1 M HCl solution. The organic was dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was chromatographed on silica gel using methlene chloride and hexane (1:1) to give an oil. A solution of methyl 3-chloro-4-(3-(3-phenyl-7-cyclopropylmethyl-6-benz-[4,5]-isoxazoloxy)-butyloxy)phenylacetic acid (0.04 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.1 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][C:2]([CH3:1])=[N:11]2
Reactant: Cc1ccc2c(O)ccnc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)ccnc2n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of the product from Example 7c (320 mg, 2.0 mmol) in 6 mL of POCl3 was heated at 50° C. with stirring for 6 h. Cooled to room temperature and quenched by pouring into ice. Adjusted to pH 10 with NH4OH and extracted with CH2Cl2. Dried over Na2SO4′ filtered and concentrated under vacuum giving the title compound as a tan solid (322 mg, 90%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=2)[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:25][C:21]1[N:20]=[C:19]([NH:18][C:17]([C:12]2[N:13]=[C:14]([CH3:16])[S:15][C:11]=2[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=2)=[O:26])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc(Nc2sc(C)nc2C(=O)Nc2cccc(C)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cccc(NC(=O)c2nc(C)sc2Nc2cccc(CO)c2)n1

Procedure:
The title compound, MS (ISP): m/e=354.9 (M+H+), was prepared by reduction of 3-[2-methyl-4-(6-methyl-pyridin-2-ylcarbamoyl)-thiazol-5-ylamino]-benzoic acid methyl ester (prepared as illustrated in example 147) with lithium aluminium hydride, as described for example 142.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:39][CH:36]3[CH2:38][CH2:37]3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2
Reactant: BrCC1CC1
Product: COc1ccc(CC2c3cc(OCC4CC4)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropylmethyl bromide
Reaction SMILES: [NH2:1][C@@H:2]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:7][CH2:6]1)=[O:4].[CH3:35][C:36]([CH3:38])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([N:11]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:36]([CH3:38])[CH3:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:6][CH2:7]2)=[CH:22][CH:21]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@H](CC(C)C)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of (S)-2-Amino-1-{4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl}-4-methyl-pentan-1-one (Example 20) (0.20 g, 0.43 mmol) and acetone (25 mg, 0.43 mmol) in CH2Cl2 (4 mL) was cooled to 0° C., treated with NaBH(OAc)3, allowed to warm to room temperature as ice melted and stir overnight. The reaction was diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 5% MeOH/CH2Cl2 to give 176 mg (81%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH:5]=O.[NH3:19]>[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][NH2:19]
Reactant: N
Reactant: COc1ccc(Oc2ccc(C=O)cc2F)cc1
Agent: [Ni]
Product: COc1ccc(Oc2ccc(CN)cc2F)cc1
Temperature: 35 °C
Reaction time: 9 h

Procedure:
73.9 mg (0.3 mmol) of 3-fluoro-4-(4-methoxy-phenoxy)-benzaldehyde are dissolved in 5 ml of methanolic ammonia, combined with Ra—Ni and shaken for about 9 hours at 35° C. and 3 bar H2 pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][O:24][C:25](=[O:47])[C@@H:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:10]([C:8]3[O:9][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: COc1c(Br)ccc2oc(C(=O)O)c(C)c12
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(Br)c(OC)c4c3C)cc2)cc1)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To 40 mg (0.14 mmol) of 5-bromo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 0.5 mL of oxalyl chloride and the mixture was refluxed for 2 h, then the excess oxalyl chloride was removed by vacuum. The residue was dissolved in 0.5 mL of dichloromethane and was added to a mixture of 92 mg (0.25 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester, 34 mg (0.28 mmol) of 4-(dimethylamino)pyridine and 1 mL of dichloromethane in an ice/water bath. The mixture was stirred at 0° C. for overnight. The mixture was diluted with dichloromethane and was washed with 2N HCl, and water. Removal of the solvent from the organic solution gave 20 mg (23% yield) of (S)-2-{4′-[(5-bromo-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccco1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1ccco1
Yield: 58.9 %

Procedure:
This compound was synthesized from 2-furaldehyde (1.92 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (2.95 g, 59%) as white crystals (mp 45-46° C.); IR: 3450-2500 cm-1 ; 1H-NMR: 1.33 (m, 8 H), 1.46 (m, 2 H), 1.65 (m, 2 H), 2.34 (t, 2 H), 2.45 (m, 2 H), 5.55 (m, 1 H), 6.18 (d, 1 H), 6.25 (d, 1 H), 6.38 (d, 1 H), 7.38 (s, 1 H), 9.80 (bs, 1 H). Anal. Calcd. for C15H22O3 :C, 71.97, H, 8.86%; Found: C, 71.93, H, 8.87%. Z:E=43:57.
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=2
Reactant: C[O-]
Reactant: COCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 65 °C

Procedure:
8-Bromo-2-{[2-(methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.4489 g) was suspended in dry methanol (11.5 mL) and then treated with 25% (w/v) sodium methoxide in methanol (2.5 mL). The reaction mixture was heated to reflux (65° C., externally) were upon a solution was obtained. After 4 hours the reaction mixture was concentrated under reduced pressure and saturated aqueous ammonium chloride (100 mL) was added. This was then extracted with ethyl acetate (100 mL, twice). The organic layers was separated, combined and washed with brine (100 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. This was then evaporated under reduced pressure to give the title compound as a white solid (1.2032 g) after placing under high vacuo, overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[C:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1)#[N:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cc(Br)cc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1cc(B(O)O)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of 3-bromonaphthalene-1-carbonitrile (0.69 g) and triisopropyl borate (0.89 g) in tetrahydrofuran (10 mL) was added n-butyl lithium (1.6 mL, 2.63 mol/L heptane solution) at −78° C. under an argon atmosphere. After warming to room temperature, the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated ammonium chloride aqueous solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated ammonium chloride aqueous solution and brine, dried over magnesium sulfate, and concentrated. The residue was suspended in n-hexane, and the solid was collected by filtration. The obtained solid was suspended in water. The suspension was acidified with hydrochloric acid, and the mixture was stirred for 30 minutes. The solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.49 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23]>C(O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:20]([OH:19])[CH:21]=3)=[C:3]([C:17]#[N:18])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: Cc1ccc(N)cc1O
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(C)c(O)c3)c2cc1OC
Yield: 54.8 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile, 30 ml ethanol, and 281 mg (2.28 mmol) 3-hydroxy-4-methylaniline was heated to reflux under N2 overnight. Removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and slurried residue in hexane. Collected solids, washed with water, and dried in vacuo, giving 364 mg off-white solid: mass spectrum (electrospray m/e): M+H=349.9.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[O:13][C:12]=2[C:24]=1[CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].[CH:33](N1CCCCC1)=[O:34].Cl>O1CCCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]([CH3:17])[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:24]([CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:12]=3[O:13][C:14]=2[C:21]=1[CH2:33][OH:34]
Reactant: COCCOCOCc1c(OC)ccc2c1Oc1cc(OC)ccc1N2C
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCCOCOCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CO)N2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
8.9 ml of n-butyllithium solution were added under argon at -78° to a solution of 4.10 g (10.92 mmol) of 3,7-dimethoxy-4-[[(2-methoxyethoxy)methoxy]methyl]-10-methyl-10H-dibenzo-[b,e][1,4]oxazine in 10 ml of tetrahydrofuran and 40 ml of diethyl ether. The reaction mixture was brought slowly to 0° and stirred for 1.5 hours, whereupon the suspension was treated with 1.82 ml (1.5 eq.) of N-formylpiperidine, stirred at 0° for 30 minutes and poured into 100 g of ice, 100 ml of 0.1N hydrochloric acid solution and 150 ml of diethyl ether. The aqueous phase was extracted three times with chloroform and the combined organic phases were dried over MgSO4 and evaporated. The reddish residue was dissolved in 50 ml of tetrahydrofuran and treated at 0° under argon with 5 ml of lithium borohydride solution (2M in tetrahydrofuran). The reaction mixture was stirred at 0° for 30 minutes and then poured into 50 g of ice, 50 ml of saturated ammonium chloride solution and diethyl ether. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over MgSO4 and evaporated. The residue was chromatographed on 200 g of silica gel with ethyl acetate/hexane (2:1), whereupon, after drying in a high vacuum, 3.90 g (88.1%) of 3,7-dimethoxy-6-[[(2-methoxyethoxy)-methoxy]methyl]-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-methanol were obtained as a colourless solid of m.p. 68°-70°.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([F:15])=[C:6]([F:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9](F)=[O:10].Cl>O1CCOCC1>[F:13][C:7]1[C:6]([F:14])=[C:5]([F:15])[C:4]([Cl:3])=[CH:12][C:8]=1[CH2:9][OH:10]
Reactant: O=C(F)c1cc(Cl)c(F)c(F)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1cc(Cl)c(F)c(F)c1F
Yield: 88.5 %

Procedure:
62 g of NaBH4 are initially introduced into 320 ml of dioxane. A solution of 319 g of 5-chloro-2,3,4-trifluorobenzoyl fluoride in 640 ml of dioxane is run into this, at the reflux temperature, over the course of 6 hours. After boiling under reflux for a further hour, the mixture is poured onto ice, the pH is adjusted to 1 with dilute hydrochloric acid, and the organic phase is extracted with methylene chloride and then distilled: 261 g of 2,3,4-trifluoro-5-chlorobenzyl alcohol of boiling point 109° C./12 mbar are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-:10].[Na+].S(=O)(=O)(O)O.I([O-])(=O)(=O)=O.[Na+]>C(#N)C.O>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(CCl)c1ccccc1
Temperature: 80 °C
Yield: 55 %

Procedure:
Acetophenone (1 mmol) was treated with sodium chloride (1.2 mmol) in acetonitrile: water (2:1, 6 ml). 20% Sulfuric acid (5 ml) and sodium periodate (20 mol %) was added to the reaction mixture. The mixture was heated at 80° C. under inert atmosphere for 6 h. The product was purified by column chromatography to give α-chloroacetophenone (55%).
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[CH:19]=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:30][S:31]SC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(Cl)Cl.C1COCC1>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19]([S:31][CH3:30])=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cn1c(=O)c2cn(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: CSSC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (52 mg, 0.132 mmol) and methyl disulfide (12 μL, 0.13 mmol) are dissolved in 2 mL of anhydrous CH2Cl2, and then 1.0 M LiHMDS (190 μL, 0.19 mmol) in THF is added dropwise. The reaction mixture is stirred at room temperature for 30 min, and then quenched with saturated ammonium chloride aqueous solution. After routine workup, the obtained crude product is purified by silica gel column chromatography to give pure product as off-white solids. MS (ESI) m/z 440.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10](S(C)=O)[N:9]=[C:8]([NH2:15])[N:7]=1.[OH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1cc(-c2ccco2)nc(N)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Nc1nc(OCCc2ccccn2)cc(-c2ccco2)n1
Temperature: 100 °C
Yield: 34.8 %

Procedure:
To a stirred suspension of 500 mg (2.24 mmol) 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine in 20 ml DME was added 0.50 ml (4.48 mmol) 2-(2-hydroxyethyl)pyridine and 0.84 ml (5.60 mmol) DBU and the mixture heated at 100° C. for 72 hours. The reaction mixture was then cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether afforded 220 mg (35%) 4-furan-2-yl-6-(2-pyridin-2-yl-ethoxy)-pyrimidin-2-ylamine as a white crystalline solid. ES-MS m/e (%): 283 (M+H+, 100).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[OH:18].C(=O)([O-])O.[Na+]>C(Cl)Cl.O1CCOCC1>[Br:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C@@H:13]2[O:18][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: O[C@H]1CCc2c(Br)cccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1

Procedure:
3,4-dihydro-2H-pyran (10.6 mL) was dissolved in methylene chloride (16.2 mL), and to the resultant solution, a 4M hydrogen chloride solution in 1,4-dioxane (31.1 μL) was added, and to the resultant reaction mixture, (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that is commercially available or can be obtained by a publicly known method was added, followed by stirring the resultant reaction mixture at room temperature for 3 hours. To the reaction mixture, a saturated sodium hydrogen carbonate aqueous solution (60 mL) was added, followed by extracting the resultant reaction mixture with methylene chloride (60 mL), and the organic phase was washed with a saturated saline (60 mL), followed by drying the organic phase over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure, followed by purifying the resultant residue by silica gel column chromatography (eluate; n-hexane:ethyl acetate=95:5), and from the resultant, the solvent was distilled off under reduced pressure to obtain the subject compound (15 g). The compound is a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:12][S:13]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: OCCOc1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(F)cc1

Procedure:
As for Example 56, 12.5 g of 2-(p-fluorophenoxy) ethanol is reacted with 7 ml of methanesulfonyl chloride in 100 ml of dichloromethane in the presence of 23 ml of triethylamine. The product (18 g) is obtained as a colorless liquid.