Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.C(O[CH:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[N+](C1C=CC(OP([O-])(OC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:17]3[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Agent: O=[N+]([O-])c1ccc(OP(=O)([O-])Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 170 °C

Procedure:
A finely powdered mixture of 24 (3.7 g, 16 mmol), 1,2,3,5-tetra-O-acetyl-D-ribofuranose (5.3 g, 16 mmol) and bis(p-nitrophenyl)phosphate (20 mg) was heated at 170° C. for 10 min under reduced pressure. After cooling to room temperature the brown solid mass was dissolved in EtOAc (500 mL) and washed with saturated aqueous sodium bicarbonate (3×300 mL). The dried (Na2SO4) organic layer was evaporated to yield a syrup which was purified by silica gel column chromatography (4×40 cm) using toluene-EtOAc (5:1). The resulting syrup was crystallized from ethanol to give a colorless powder: yield 6.4 g, 80%: mp 125°-126° C.: 1H NMR (DMSO-d6) δ1.99, 2.06, 2.08 (3s, 9H, acetyl), 6.07 (d, J=3.40 Hz, 1H, C1,H), and other sugar protons. Anal. Calcd. for C16H15Cl2N3O8S: C, 40.01: H, 3.15: Cl, 14.76: N, 8.75: S, 6.68. Found: C, 40.20: H, 3.31: Cl, 14.79: N, 8.61: S, 6.66.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>COCCO.[Ru]>[CH2:1]([N:8]1[C:17](=[O:19])[CH:16]2[CH:11]([NH:12][CH2:13][CH2:14][CH2:15]2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccnc1C(O)=NCc1ccccc1
Reactant: [H][H]
Agent: [Ru]
Solvent: COCCO
Product: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Yield: 90.1 %

Procedure:
47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-benzylimide (British Patent 1,086,637; Chem. Abstr. 68, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90° C. under 100 bar until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is concentrated on a rotary evaporator. 44 g of an oily crude product are obtained.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[NH2:27].CCCCCC>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[CH:21][C:20]=1[NH:27][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11]
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1N
Reactant: CC(C(=O)O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: COC(=O)c1cc(Cl)c(Cl)cc1NC(=O)C(C)c1ccccc1
Yield: 95 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (2.28 mL, 40.0 mmol), and 2-amino-4,5-dichloro-benzoic acid methyl ester (1.95 g, 8.88 mmol). After normal workup, the pure objective compound (2.97 g, 95%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=20:1): 1H NMR (200 MHz, CDCl3) δ 1.59 (d, J=7.1 Hz, 3H, CH3), 3.70-3.89 (m, 4H, CO2CH3& CH), 7.28-7.42 (m, 5H, ArH), 8.03 (s, 1H, ArH), 8.99 (s, 1H, ArH), 11.00 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)[CH2:26][C:27]([OH:29])=[O:28].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:18]([O:17][C:15]1[CH:14]=[C:11]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
3.18 g. of 3,5-dibenzyloxy-benzaldehyde [L.A. Svensson, Kem. Tidskr., 87, 289 (1975)] and 1.6 g. of malonic acid are stirred in a mixture of 8 ml. of pyridine and 0.1 ml. of piperidine for 3 hours at 100° C. 25 ml. of 15% hydrochloric acid are then added, whereafter the product is filtered by suction, washed with water and dried. The crude product is crystallized from 150 ml. of methanol and 3 g. of 3-(3,5-dibenzyloxy-phenyl)-propenoic acid melting at 154°-156° C. are obtained. The product is suspended in 250 ml. of abs. ether, 0.90 g. of lithium aluminum hydride is added and the mixture is heated under stirring for 5 hours. After cooling the excess hydride is decomposed by acetone and acidified with 100 ml. of 10% hydrochloric acid. The two layers are separated and the aqueous layer is shaken out with ether again, the combined organic layer is washed with water, dried on magnesium sulphate and evaporated. 2.88 g. of 3-(3,5-dibenzyloxy-phenyl)-1propanol are obtained, m.p.: after recrystallization from n-hexane: 48°-50° C. 5.47 g. of the above alcohol are dissolved in 30 ml. of abs. pyridine and 2.26 g. (1.5 ml., 0.020 mole) of methane sulfonic acid chloride are added and the mixture is poured after 30 minutes to a mixture of 300 g of ice and 75 ml. of cc. HCl. The product is extracted with 125 ml. of dichloromethane and the organic layer is washed with 2×20 ml. of saturated hydrochloric acid solution, dried above magnesium sulphate and evaporated. 6.2 g. of 3-(3,5-dibenzyloxy-phenyl)-1-methanesulfonyloxy-propane are obtained, from which 2.60 g. are heated for 15 minutes with 20 ml. of 1 N sodium methylate and the solution is poured to 220 ml. of 1% hydrochloric acid solution. The product is extracted with dichloromethane, the extract is dried and evaporated. The residue (1.9 g.) is subjected to column chromatography and as eluants benzene and methyl ethyl ketone solvents are used. 1.30 g. of 1-(3,5-dibenzyloxy-phenyl)-3-methoxy-propane are obtaned as colorless oil,
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH2:22].[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH:22][CH3:26]
Reactant: COC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(CCc2cc(OC)ccc2OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
110 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-amino benzoic acid methylester are dissolved in 6 ml of dry dimethylformamide and treated with 13 mg of sodium hydride (80% in mineral oil). After stirring for 30 minutes at room temperature, 0.2 ml of methyl iodide are added and stirring continued overnight. The solvent is distilled off in vacuo, and the residue is partitioned between aqueous ph7 buffer solution and ethyl acetate. The separated organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (hexane/ethyl acetate=7/1) to give the title compound as colourless crystals. mp: 73°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([Cl:25])=[O:21])=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
This product is prepared by refluxing for 3 hours a solution of 10 g (34.81 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, and 25.4 mL (0.348 mol) of sulfonyl chloride in 174 mL of toluene. After this time, the reaction mixture is concentrated under reduced pressure. The resulting mixture is taken up twice successively in 100 mL of toluene and then concentrated under reduced pressure. The product is used in the rest of the synthesis without a further purification step.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[F:13])[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Fc1ccccc1-c1nsc(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccccc3F)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-3-(2-fluorophenyl)-1,2,4-thiadiazole (119 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the desired product as a solid was separated by filtration, which was then recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran. Yield: 96.0 mg (40.9%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]1[CH:24]=[CH:23][CH:22]=[CH:21][C:13]=1[CH:14](O)[C:15]1[CH:19]=[CH:18]S[CH:16]=1.S(=O)(=O)(O)[OH:26].Cl>C(OCC)C>[O:26]1[CH:18]=[CH:19][C:15]([CH2:14][C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[Br:11])=[CH:16]1
Reactant: O=S(=O)(O)O
Reactant: OC(c1ccsc1)c1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Brc1ccccc1Cc1ccoc1
Temperature: 0 °C

Procedure:
Aluminum chloride (78.0 mmol) dissolved in diethyl ether (40 mL) under nitrogen was added to a suspension of lithium aluminum hydride (78.0 mmol) in diethyl ether (40 mL) under nitrogen at 0° C. To the reaction mixture was added a solution of Compound 3a (52.0 mmol) in diethyl ether (25 mL) at such a rate that reflux was maintained. After an additional 15 minutes at reflux, the reaction mixture was cooled to 0° C. and dilute 3M sulfuric acid was added dropwise until the evolution of gas stopped. The reaction mixture was then poured onto ice (100 mL) and 3N hydrochloric acid (25 mL) and then extracted with diethyl ether (2×50 mL). The combined organic phases were washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel eluted with ethyl acetate:hexane (2:98) to afford Compound 3b as an oil (Rf =0.4).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7](Br)=[CH:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][C:24]#[CH:25].Cl>C(NCC)C.C(Cl)Cl.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>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]([C:25]#[C:24][CH2:23][NH:22][CH3:21])=[CH:8][CH2:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: C#CCNC
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCNCC
Solvent: ClCCl
Product: CNCC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.7 g (10 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine hydrochloride, 0.4 g (0.6 mmole) of dichlorobis(triphenylphosphine)palladium (II), 0.2 g (1 mmole) cuprous iodide and 2 ml (excess) of 97% N-methylpropargylamine in 50 ml of 98% diethylamine and 100 ml of methylene chloride was stirred at room temperature under nitrogen for 24 hr. The reaction was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride and extracted with dilute ice cold hydrochloric acid. The acid extract was made alkaline with dilute ice cold sodium carbonate and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography (silica gel, 20 g; eluent, 20% ether in methylene chloride followed by 10% methanol in methylene chloride) gave from the latter eluent an amber oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from isopropanol to give end product which when recrystallized from isopropanol gave tan crystals, mp 169°-175° C. dec.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13](O)=[O:14])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.B.C1COCC1>CO>[CH:1]1([C:7]2[O:8][C:9]([CH3:16])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(C2CCCCC2)nc1CC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(C2CCCCC2)nc1CCO
Temperature: 50 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
1.920 g of the above prepared (2-cyclohexyl-5-methyl-oxazol-4-yl)-acetic acid (8.60 mmol) was dissolved in 56 ml of abs. THF and treated at 0° C. with 21.5 ml of 1M BH3THF (2.5 eq.). The reaction mixture was then kept over weekend at ambient temperature. 3.5 ml of MeOH was added and the mixture stirred for 3 h at ambient temperature and for 3 h at 50° C. to liberate the free alcohol. Removing of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=4/6) yielded finally 1.314 g of the title compound as colorless oil.
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.[CH3:8][C:9]1[C:26]2[C@:21]([CH3:28])([CH2:22][CH2:23][C:24](=[O:27])[CH:25]=2)[C@@H:20]2[C@H:11]([C@H:12]3[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[C:14](=[CH2:30])[CH2:13]3)[CH:10]=1.C(O)(=O)C.P([O-])([O-])([O-])=O>C1COCC1.CO.C(OCC)(=O)C>[C:3]([C@:15]1([OH:29])[C:14](=[CH2:30])[CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:21]1([CH3:28])[C:26](=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:9]([CH3:8])=[CH:10]3)#[CH:4]
Reactant: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O
Reactant: [Li]CCCC
Agent: C#C
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#C[C@]1(O)C(=C)C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 3.5 h

Procedure:
Acetylene saturated THF (45 ml, 4.2 equivalents) was cooled to -72° over 5 min while addition of acetylene continued. The acetylene bubbling was stopped and n-butyl lithium (1.55M, 16.6 ml, 4.0 equivalents) was added over 15 min keeping the temperature less than -65°, mostly at -68°. The mixture was cooled to -90° and added to 6-methyl-16-methyleneandrosta-4,6-diene-3,17-dione. (IIIA, Example 11, 2.0 g) in THF (10 ml) previously cooled to -105° via an insulated teflon canula over about 3 min. The mixture was exothermically warmed to -87° and was recooled to -90° (bath at -93°). After 3.5 hr TLC indicated the reaction was complete. Acetic acid (1.84 ml, 5 equivalents) was added in methanol (10 ml) previously cooled to -98°. The mixture was warmed to 20°-25° and phosphate buffer (20 ml) and ethyl acetate (20 ml) were added. The layers were separated. The organic layer was washed with buffer/saline (1/1). The aqueous layer was back extracted with ethyl acetate which was washed with saline. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to an oil. Ethyl acetate was added along with a seed crystal and the mixture sat over night at 20°-25°, and then -20° for 4 hr. The crystals were obtained by filtration, washed with ethyl acetate/hexane: (1/1) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[F:12][C:13]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:14]=1[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH:23][S:24]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH:20]=[C:19]([O:34][CH3:35])[N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:12][C:13]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:14]=1[CH2:15][S:16][C:17]1[N:22]=[C:21]([NH:23][S:24]([N:27]2[CH2:28][CH2:29][CH:30]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:31][CH2:32]2)(=[O:25])=[O:26])[CH:20]=[C:19]([O:34][CH3:35])[N:18]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCN(C)CC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-piperazine (0.13 mL) in DCM (2 mL) was added to a solution of acetic acid (0.03 mL) and N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of example 148, step iii) (0.10 g) in DCM (2 mL). The solution was stirred at room temperature for 1 h then sodium triacetoxyborohydride (0.24 g) was added in portions. The mixture was stirred at room temperature overnight then the DCM was evaporated and 3M aqueous sodium hydroxide (6 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water, saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by reverse phase HPLC (gradient 25-95% acetonitrile in 0.1% aqueous ammonium acetate) to afford the title compound as a white powder. Yield: 22 mg
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].[CH3:11][C:12]1[CH:16]=[CH:15][O:14][C:13]=1[C:17]([C:19](=[C:22](SC)[S:23][CH3:24])[C:20]#[N:21])=O>CN(C=O)C>[NH2:7][C:6]1[N:8]=[C:17]([C:13]2[O:14][CH:15]=[CH:16][C:12]=2[CH3:11])[C:19]([C:20]#[N:21])=[C:22]([S:23][CH3:24])[N:5]=1
Reactant: CSC(SC)=C(C#N)C(=O)c1occc1C
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2occc2C)c1C#N
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
6.32 g (39.5 mmol) guanidine carbonate was added portionwise to a stirred suspension of 0.7 g (17.5 mmol, 60% dispersion in mineral oil) sodium hydride in 70 ml DMF under argon at room temperature and stirring continued at 40° C. for 30 minutes. A solution of 7.4 g (29.2 mmol) 2-(3-methyl-furan-2-carbonyl)-3,3-bis-methylsulfanyl-acrylonitrile in 15 ml DMF was then added dropwise and the reaction mixture heated at 100° C. for 30 minutes. The reaction mixture was then poured onto 2 l ice-water, and the precipitate collected by filtration and dried in vacuo to afford 6.12 g (85%) 2-amino-4-(3-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow solid. ES-MS m/e (%): 247 (M+H+, 100).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 515.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20](OC(C)C)[O:19]1>O1CCCC1>[CH3:17][C:18]1([CH3:29])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)[O:19]1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3ccccc3)o2)OC1(C)C
Temperature: -78 °C
Yield: 24.9 %

Procedure:
To a solution of 2-phenylfuran (1.20 g, 8.32 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n-BuLi (4.9 mL, 2.5 M solution in hexane) dropwise with stirring at −78° C. under nitrogen. The resulting solution was warmed slowly to −40° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.10 g, 16.66 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 4,4,5,5-tetramethyl-2-(5-phenylfuran-2-yl)-1,3,2-dioxaborolane (560 mg, 25%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCl.[Br:14]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe].O>[Br:14][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[OH:10]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
139.40 g (64.7 mmol) of 4-nitrophenol and 130 ml of dichloromethane are introduced into a three-necked flask under an argon atmosphere. The mixture is cooled to 0° C. and 3.31 ml (67.7 mmol) of bromine are added dropwise. The reaction medium is stirred for one hour at 0° C., 360 mg (6.5 mmol) of iron powder are then added and this mixture is stirred for sixteen hours at room temperature. The reaction medium is poured into water, a saturated sodium thiosulphate solution is added, this mixture is extracted with dichloromethane and washed with water, the organic phase is separated out after settling has taken place and dried over magnesium sulphate, and the solvents are evaporated off. 13.50 g (96%) of the expected compound are collected in the form of a beige-coloured powder with a melting point of 105–107° C.