Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])=[CH:37][CH:36]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)Cc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 51.8 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added 4-chlorophenylacetyl chloride (267 mg, 1.41 mmol) and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a orange foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a yellow syrup that was triturated with diethyl ether to afford the title compound 0.230 g, 52%) as a yellow solid, m.p. 83° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:25])([F:24])[F:13])=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL:25 mL) was purged with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol) the reaction was heated at 100° C. overnight. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous. sodium sulfate, filtered and concentrated in vacuo to give a brown oil. Purification by flash chromatography with a solvent gradient of 25% to 50% dichloromethane in hexane provided 2.0 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccs2)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1cccs1

Procedure:
From 2-amino-4-methanesulfinyl-6-thiophen-2-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in dioxane. EI-MS m/e (%): 309 (M+, 53), 308 ([M—H]+, 48), 292 ([M—NH3]+, 32), 108 (100), 92 (50), 65 (49).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C.C(OCC)(=O)C>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC(=O)OCCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
A solution of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (10 g, 0.35 mol), 5-bromopentyl acetate (8.15 g) and potassium carbonate (33.6 g) in methyl ethyl ketone (200 ml) is refluxed for 2 hours. The reaction medium is treated with water and ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].CS([C:15]1[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=1)(=O)=O.C(O)(=O)C>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:15]2[S:19][N:18]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:16]=2)=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1cc(C(F)(F)F)ns1
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(Cc1cc(C(F)(F)F)ns1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The oil of a 4.0 g (100 mmol) portion of 60 percent in mineral oil sodium hydride was removed by triple extraction with hexane and was replaced with 100 mL of tetrahydrofuran. 4-Chloroacetophenone (4.33 g, 28 mmol) was added and the mixture was heated at reflux with stirring for 1 hr and then allowed to cool. 5-Methylsulfonyl-3-(trifluoromethyl)isothiazole (4.57 g, 19.8 mmol) dissolved in a small amount of tetrahydrofuran was added and the mixture was heated at reflux with stirring for 3 hr and then allowed to cool. The mixture was next acidified with 60 mL of 10 percent aqueous acetic acid and the layers that formed were separated. The aqueous layer was extracted with 2×100 mL of ether and the organic fractions were combined, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a residue. This residue was washed with hexane and crystallized from a 1:1 mixture of dichloromethane and hexane to obtain 3.19 g (53 percent of theory) of the title compound as a solid melting at 109°-110° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:3][CH2:4][C:6]1[CH:15]=[CH:14][C:9]2[S:10][CH:11]=[C:12]([CH3:13])[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2scc(C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1csc2ccc(CO)cc12
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A solution of 3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (14.44 g.) in dry ether (50 ml.) was added dropwise with stirring to a mixture of lithium aluminium hydride (5.32 g.) in dry ether (450 ml.) under an atmosphere of dry nitrogen. Sufficient heat was applied during the addition to maintain gentle reflux. The mixture was heated under reflux with stirring for 3 hours and then cooled. The excess of lithium aluminium hydride was decomposed by the cautious addition with stirring of water (5.3 ml.) followed by 5N sodium hydroxide solution (5.3 ml.) and finally more water (16 ml.). The mixture was filtered and the filtrate was dried (Na2SO4) and evaporated to give an oil which crystallized on standing. The solid was crystallized from ether/petrol (b.p. 40°-60°) to give 5-hydroxymethyl-3-methylbenzo[b]thiophene (8.93 g.), m.p. 51°-53°.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[CH2:11]([O-:13])[CH3:12].[Na+]>C1COCC1>[CH2:11]([O:13][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)[CH3:12]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a mixture of 4-nitropyridine 1-oxide (50 g, 357 mmol) in THF (500 mL) was added sodium ethanolate (48.6 g, 714 mmol). The mixture was stirred at 25° C. for 16 h. The reaction residue was concentrated. The crude material was purified by silica column chromatography (DCM/MeOH=25:1). All fractions found to contain product by TLC (DCM/MeOH=25:1, Rf=0.6) were combined and concentrated to yield a dark red solid of 4-ethoxypyridine 1-oxide (25 g, 162 mmol, 45.3% yield): 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.11-7.10 (m, 2H), 4.21-4.15 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); ES-LCMS m/z 140.0 (M+H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1>>[CH:28]1([CH2:31][C:32]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:33])[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (86 mg, 83%), MS (ISP) m/z=413.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclopropyl-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10](O)=O)[NH:5][C:4]=2[C:3]=1[N:13]([CH3:22])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15].C([S:30][CH:31]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[CH2:32][NH2:33])C1C=CC=CC=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.C(#N)C.O1CCCC1>[CH3:36][O:35][CH:34]([O:37][CH3:38])[CH:31]1[S:30][C:10]([C:6]2[NH:5][C:4]3[C:3]([N:13]([CH3:22])[S:14]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)(=[O:16])=[O:15])=[C:2]([CH3:1])[S:9][C:8]=3[CH:7]=2)=[N:33][CH2:32]1
Reactant: Cc1sc2cc(C(=O)O)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCl
Product: COC(OC)C1CN=C(c2cc3sc(C)c(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
To a mixture of 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (1.0 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (720 mg), 1H-1,2,3-benzotriazol-1-ol (450 mg), tetrahydrofuran (10 mL) and acetonitrile (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (570 mg), and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a colorless oil. To a solution of triphenylphosphine oxide (252 mg) in dichloromethane (3 mL) was slowly added trifluoromethanesulfonic anhydride (76 μL) at 0° C., the mixture was stirred for 10 min, and the colorless oil was added. The mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-{5-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl}-N-methylthiophene-2-sulfonamide (245 mg, yield 27%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 185° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][C@H:18]1[C@@H:23]([N:24]=[N+:25]=[N-:26])[C@@H:22]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:21][CH:20]=[CH:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:36]([OH:39])(=[O:38])[CH3:37].[C:40]([OH:43])(=[O:42])[CH3:41].IC1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[C:36]([O:39][C@@H:19]1[C@@H:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:23]([N:24]=[N+:25]=[N-:26])[C@@H:22]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:21][C@H:20]1[O:43][C:40](=[O:42])[CH3:41])(=[O:38])[CH3:37]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)C=CO[C@@H]1COCc1ccccc1
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CCOCC
Product: CC(=O)O[C@@H]1O[C@H](COCc2ccccc2)[C@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reaction time: 0.42 h
Yield: 85.3 %

Procedure:
Boron trifluoride diethyl etherate (74.0 μL, 0.636 mmol, 0.219 equiv) was added to a solution of glycal 218 (1.020 g, 2.904 mmol, 1.000 equiv) and iodobenzene diacetate (1.119 g, 3.474 mmol, 1.196 equiv) in dichloromethane (36 mL) in a cold bath at −50° C. After 25 min, the yellow solution was transferred to a cold bath at −25° C. and stirred for an additional 30 min Triethyl amine (2.0 mL) was added, and the resulting suspension was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was extracted with dichloromethane (30 mL), and the combined organic layers were dried with magnesium sulfate and purified by silica gel chromatography (hexane/ethyl acetate 4:1 to 3:1) to afford 222 (1.163 g, 2.477 mmol, 85% yield) as a yellow solid. Rf=0.25 (hexane/ethyl acetate 3:1); 1H NMR (400 MHz, CDCl3) δ 7.41-7.28 (m, 10H), 5.51 (d, J=8.3, 1H), 5.30 (dd, J=9.8, 8.4, 1H), 4.74 (d, J=12.2, 1H), 4.56 (d, J=12.3, 1H), 4.54 (s, 2H), 4.08 (dd, J=3.6, 1.1, 1H), 3.74 (td, J=6.7, 1.3, 1H), 3.69 (dd, J=9.8, 3.6, 1H), 3.63 (d, J=6.8, 2H), 2.06 (s, 3H), 2.00 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 169.50, 169.38, 137.51, 137.25, 128.73, 128.69, 128.32, 128.23, 128.20, 127.92, 92.47, 78.73, 73.86, 72.60, 72.23, 69.78, 67.82, 59.10, 20.96, 20.88; FTIR (neat film) 2920.8, 2107.7, 1755.9, 1454.8, 1368.4, 1232.5, 1214.6, 1059.1, 739.3, 698.4 cm−1; HRMS (ESI) m/z: Calcd for C24H27N3O7Na (M+Na+) 492.1747, found 492.1755.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1.O.Cl>C(O)CCC>[OH2:4].[ClH:1].[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: OC(CCC1NCCc2ccccc21)COc1ccccc1Cl

Procedure:
A mixture of 11.8 g. (0.05 mole) of 1-(2-chlorophenoxy)-2-hydroxybutyl chloride, 13.3 g. (0.1 mole) of 1,2,3,4-tetrahydroisoquinoline and 100 ml. of n-butanol was heated in a steel bomb at 120° C. for 24 hr. The reaction mixture was filtered at room temperature, the filtrate was mixed with 200 ml. 3N hydrochloric acid and extracted twice with 100 ml. isopropyl ether. The aqueous acidic solution was made basic and extracted with isopropyl ether and treated with ethereal hydrogen chloride. Recrystallization with isopropanol yielded 6 g. of the hydrochloride hydrate of the product which melted at 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Clc1cc(Cl)c(CBr)cn1
Temperature: 132 °C
Reaction time: 16 h
Yield: 125.3 %

Procedure:
2,4-dichloro-5-methylpyridine (13.64 g, 82.50 mmol), N-bromosuccinimide (15.42 g, 86.63 mmol) were dissolved in chlorobenzene (300 mL). 2,2′-azobis(isobutyronitrile) (1.355 g, 8.250 mmol) in chlorobenzene (160 mL) was added slowly in two times: first approximately a third of the total amount at room temperature, then the rest dropwise (over 40 min) at 132° C. The reaction mixture was stirred at 132° C. for 16 h. The reaction mixture was washed with a saturated sodium sulfite solution (organic layer at the top), then with a saturated sodium bicarbonate solution (organic layer at the bottom). The organic phase was dried with sodium sulfate, then filtered and concentrated. A crude material was obtained as a yellow oil (24.9 g). It was purified by flash chromatography (Heptanes/AcOEt gradient from 0 to 10% AcOEt) to yield pale yellow crystals (13.84 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].COC(C)(C)C.Cl[CH2:20][C:21]([O:23][CH3:24])=[O:22].C[O-].[Na+]>C(O)(=O)C>[CH3:24][O:23][C:21]([CH:20]1[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH2:10][CH3:11])([CH3:8])[O:9]1)=[O:22]
Reactant: COC(=O)CCl
Reactant: CCC(C)(CCCC(C)=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CCC(C)(CCCC1(C)OC1C(=O)OC)OC
Temperature: 0 °C
Yield: 67.5 %

Procedure:
860 g 6-Methoxy-6-methyl-2-octanone, 4 l tert.-butyl methyl ether and 648 g methyl chloroacetate were cooled to 0° C. under a blanket of nitrogen. Under further cooling, 350 g sodium methoxide was added in 6 portions over 20 minutes. The mixture was then stirred at room temperature till no more consumption of the ketone was observed (GC). After cooling to 0° C., 1 l 5% acetic acid (w/w) was added and the phases were separated. The aqueous phase was extracted with tert.-butyl methyl ether (500 ml). The combined organic phases were washed with water, concentrated KHCO3 solution, concentrated NaCl solution and dried over MgSO4. The yellow oil which remained after the removal of the solvent was distilled over a small Vigreux-column to give 823 g of 3-(4-methoxy-4-methyl-hexyl)-3-methyl-oxirane-2-carboxylic acid methyl ester (mixture of isomers, boiling point: 115°-128°/0.3 Torr=0.399 mbar).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9]O)[CH2:7][OH:8].Cl>>[CH:3]([CH:1]1[O:8][CH2:7][C:6]([CH3:11])([CH3:9])[CH2:5][O:2]1)=[CH2:4]
Reactant: CC(C)(CO)CO
Reactant: C=CC=O
Agent: Cl
Product: C=CC1OCC(C)(C)CO1
Temperature: 30 °C

Procedure:
2-Ethenyl-5,5-dimethyl-1,3-dioxane was prepared by adding 15.4 g. of acrolein (9.275 mole) and 26.0 g. (0.25 mole) 2,2-dimethyl-1,3-propanediol to a 100 ml. round bottom flask equipped with magnetic stir bar and thermocouple. Hydrochloric acid (0.1 ml. 37%) was added to the reduction and the temperature dropped to about 5° C. After all of the diol was dissolved, the reaction exothermed to approximately 45° C. After the reaction was cooled to 30° C., the mixture was placed in a separatory funnel. The lower aqueous layer was removed and the organic layer simultaneously neutralized and dried with excess sodium carbonate (anhydrous). The material was filtered and distilled (Bp 40° C. at 10 mm/Hg) to give a water clear liquid.
Reaction SMILES: [C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42].N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1([CH2:13][O:14][C:15]2[C:23]([CH:24]3[CH2:25][CH2:26]3)=[CH:22][C:18]([C:19]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:21])=[C:17]([F:27])[CH:16]=2)[CH:10]2[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]1[CH2:12]3)[CH2:11]2)#[N:2]
Reactant: CS(N)(=O)=O
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.5 %

Procedure:
To a solution of 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.17 g, 0.45 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (0.15 g, 0.89 mmol). The reaction solution was heated to reflux under a nitrogen atmosphere for 15 minutes and cooled to ambient temperature. To this reaction solution methanesulfonamide (0.10 g, 1.05 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL, 1.40 mmol) was added. The mixture was stirred at ambient temperature for 2.5 hours, then diluted with ethyl acetate (10 mL), washed with 1 M hydrochloric acid (2×10 mL) and brine (2×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless powder (0.019 g, 10%): 1H NMR (300 MHz, DMSO-d6) δ 11.94 (br s, 1H), 7.16-7.12 (m, 2H), 4.46 (s, 2H), 3.31 (s, 3H), 2.16-1.79 (m, 11H), 1.70-1.61 (m, 4H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H); MS (ES−) m/z 445.2 (M−1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
550 mg of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 381 mg of furfurylamine are initially charged in 100 ml of methanol and treated with 1 ml of glacial acetic acid. The mixture is stirred at room temperature for 15 min, briefly brought to the boil and then, at 0° C., admixed a little at a time with 493 mg of sodium cyanoborohydride. The mixture is stirred overnight at room temperature and then treated with 1 N HCl and stirred for 30 min. The mixture is then made basic using Na2CO3 solution and extracted 2× with ethyl acetate. The organic phase is washed (sat. NaCl solution) and dried (MgSO4). Concentration and chromatographic purification (dichloromethane/ethyl acetate 10+1) gives 430 mg of a colourless oil.