Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(O[N:7]1[CH2:15][CH:14]2[CH:9]([C:10]([F:29])([F:28])[CH2:11][CH2:12][C:13]2([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]1=C=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:22]1([C:13]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11][C:10]([F:29])([F:28])[CH:9]3[CH:14]2[CH2:15][NH:7][CH2:8]3)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)ON1CC2C(C1=C=O)C(F)(F)CCC2(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: FC1(F)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
20 cm3 of dioxane and 20 cm3 of 6.3N hydrochloric acid are added to 1.8 g of (3aRS,7aRS)-2-tert-butyloxy-carbonyl-4,4-diphenyl-7,7-difluoroperhydroisoindole. After stirring for 20 hours at room temperature, the white suspension obtained is concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is washed with diisopropyl oxide, the solid obtained is drained and then dried. 1.51 g of (3aRS,7aRS)-4,4-diphenyl-7,7-difluoroperhydroisoindole hydrochloride are obtained in the form of a white solid.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31].[H-].[Na+].I[CH3:35]>CN(C)C=O>[ClH:1].[CH3:35][O:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31]
Reactant: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2Cc3cc(C(F)(F)F)ccc3N(CCN(C)C)C(=O)[C@H]2OC)cc1
Reaction time: 0.5 h

Procedure:
A solution of (cis)-3-(hydroxy)-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one, monohydrochloride (0.81 g, 1.92 mmol) in 21 ml of dimethylformamide was treated with sodium hydride (0.23 g, 5.76 mmol of a 60% mineral oil dispersion) at room temperature under argon. Stirring was continued for 30 minutes. The temperature was lowered to 0° C., iodomethane was added (0.13 ml, 2.11 mmol) and the reaction was continued for 11/2 hours at 0° C. The reaction was quenched at 0° C. with water. Dimethylformamide and water were removed in vacuo. Hexane and 1M hydrochloric acid were added, the aqueous layer was washed twice with hexane, made basic with saturated aqueous potassium carbonate solution and washed three times with ethyl acetate. The ethyl acetate layers were washed with brine, dried over sodium sulfate, and evaporated in vacuo to yield 0.95 g of an oil. This material was dissolved in a minimal amount of chloroform, treated with saturated hydrogen chloride-ether solution, evaporated in vacuo and triturated with ether/ethyl acetate/methanol (80:15:5) to yield 0.67 g of a white solid, melting point 148° C. (dec).
Reaction SMILES: Cl.Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:34]([O:38][C:39](=[O:42])[CH:40]=C)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:42])[CH2:40][CH2:33][N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:10]2[N:9]=[N:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:18]=3)[CH:11]=2)[CH2:28][CH2:29]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Product: CCCCc1nnc(OC2CCN(CCC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine (Example 14, 0.244 mmol, 100 mg) and acrylic acid tert-butyl ester (2 mL) may be stirred at room temperature for 20 h. The organic solvent may be removed in vacuo and the residue is purified by column chromatography on silica gel using 1-2% of MeOH in DCM to give 3-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidin-1-yl}-propionic acid tert-butyl ester.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](N(OC)C)=[O:15])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[CH:14]([C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
0.9 g of tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine-1-carboxylate is dissolved in 31 ml of diethyl ether under N2. The reaction medium is placed at 0° C. and 3.41 ml of 1N lithium aluminium hydride in tetrahydrofuran is carefully added. The mixture is stirred at 0° C. for 2 h. After hydrolysis with an aqueous potassium sulphate solution, extraction is carried out with diethyl ether until the aqueous phase is completely depleted. Drying over MgSO4 and concentration to dryness are carried out. The crude obtained is chromatographed on silica gel, elution being carried out with a 9/1 mixture of dichloromethane and methanol. 0.45 g of tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate is obtained.
Reaction SMILES: C(N1C[CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(C)C.[OH-].[Na+]>Cl>[CH:19]([NH:18][CH:17]1[CH2:5][CH2:6][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[NH:26][C:25](=[O:27])[C:24]4[C:19](=[CH:20][C:21]([O:30][CH3:31])=[CH:22][C:23]=4[O:28][CH3:29])[N:18]=3)=[CH:15][CH:16]=2)[CH2:8][CH2:14]1)([CH3:24])[CH3:20]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCN(C(C)C)CC4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(CN4CCC(NC(C)C)CC4)cc3)nc2c1
Yield: 42.1 %

Procedure:
A solution of 2-(4-((4-isopropylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.470 g, 0.98 mmol) in 2N HCl (20 mL) was refluxed for 3 days. The resulting mixture was basified with 2N NaOH and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, afforded the title compound (0.090 g, 21%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.12 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 6.73 (d, J=2.3 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.50 (s, 2H), 2.86-2.92 (m, 1H), 2.73-2.77 (m, 2H), 1.85-2.01 (m, 2H), 1.72-1.77 (m, 2H), 1.09-1.38 (m, 4H), 0.94 (d, J=6.2 Hz, 6H). ESI/APCI MS m/z 437 [M+H]+.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:10]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C#N)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 30.9 %

Procedure:
A mixture of terephthalonitrile (1.50 g, 12 mmol), methyl thiosalicylate (2.95 g, 18 mmol), triethylamine (2.10 g, 21 mmol) and toluene (20 ml) was heated and refluxed under a nitrogen flow for 48 hours. The crystals precipitated were taken by filtration and recrystallized from tetrahydrofuran to give the title compound (0.98 g, 32%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.Cl[S:20]([C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21].N12CCN(CC1)CC2>C1COCC1>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:20]([C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)cc1F
Yield: 45 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (378 mg, 1.54 mmol) prepared in Example 14a, methyl 5-(chlorosulfonyl)-2,4-difluorobenzoate (500 mg, 1.85 mmol), 1,4-diazabicyclo[2.2.2]octane (208 mg, 1.85 mmol) and THF (15.0 mL), to yield the title compound (332 mg, 45%) as a pale yellow oil.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CCC)=[N:37]OC=2C)=NC=1.C(N)(C)C>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CCCC(C)c1noc(C)c1COc1ccc(C(=O)OC)cn1
Solvent: CC(C)N
Product: CCCC(C)c1noc(C)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 17 %

Procedure:
As described for example 9, 6-[5-methyl-3-(1-methyl-butyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.63 mmol), instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted using isopropylamine instead of rac-2-amino-1-propanol, to the title compound (40 mg, 17%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=346.4 [M+H]
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:23]3[C:24](=[O:33])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]3=[O:32])[S:12][CH:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc(Cl)c(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Yield: 92 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 4-(3,4-dichlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 6 & 7, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 92% yield.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[C:19]#[CH:20]>O1CCCC1>[CH2:18]([NH:21][C:15]([C:13]1[C:14]2[C:5]([CH:6]=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)=[O:16])[C:19]#[CH:20]
Reactant: C#CCN
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Solvent: C1CCOC1
Product: C#CCNC(=O)c1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A solution of 13.68 g of 9-anthroyl chloride in 30 ml of tetrahydrofuran is added at 10°-15° to a solution of 10 g of propargylamine in 60 ml of tetrahydrofuran. After stirring at room temperature for 4 hours, the solvent is removed and the residue is stirred with methylene chloride and 5% aqueous sodium bicarbonate solution. The methylene chloride layer is dried and concentrated to give 14.54 g of crude N-propargyl-9-anthramide as a solid. An analytical sample (ethanol) had a melting point of 201°-202°; H nmr spectrum: τ 1.5-2.8 (m, 9); 3.7 (broad, 1); 5.7 (d of d, 2) and 7.7 (τ, 2.5 Hz, 1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:14]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].O1CCCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:14]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(SCC(C)C)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A reaction mixture solution prepared by suspending 155.2 mg of ethyl 2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding 49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, 3 mL of water was added and extraction was performed using ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate. (2) The crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate obtained above was reduced using palladium carbon under a hydrogen atmosphere to obtain ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. (3) A reaction mixture solution prepared by suspending ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azide and 148 mg of triethyl ortho formate was heated at 70° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduce pressure, followed by purifying by a conventional method to obtain 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (4) A reaction mixture solution prepared by adding 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate to 2 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.5 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 67.9 mg of 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH2:48][CH:49]([CH3:51])[CH3:50])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[F:52]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH2:48][CH:49]([CH3:50])[CH3:51])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[F:52])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)CS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Yield: 99 %

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-Bromo-1-fluoro-4-(2-methyl-propane-1-sulfonyl)-benzene (Intermediate 131), the title compound was obtained as a colorless oil in 99% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.S(=O)(=O)(O)O.N>C(O)(=O)C>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2[N:15]=[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]3=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[CH2:13]1)[C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc(CN2CCc3nc4ccccc4c(-c4ccccc4)c3C2)cc1
Yield: 145.7 %

Procedure:
1-t-Butoxycarbonyl-4-piperidone (1.93 g, 10.2 mmol) and 2-aminobenzophenone (2.01 g, 10.2 mmol) were suspended in acetic acid (10 ml), followed by adding thereto sulfuric acid (0.1 ml), and the reaction was carried out at 120° C. for 1 hour. The reaction mixture was poured into cold aqueous ammonia, and the crystals precipitated were washed with water and recrystallized from ethanol to obtain the desired compound (2.60 g, 7.43 mmol).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH:12]1([CH2:18]O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10]
Reactant: OCC1CCCCC1
Reactant: O=C(O)Cc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Cc1ccccn1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a mixture of 422 mg of 2-pyridylacetic acid hydrochloride and 596 μl of cyclohexylmethanol in 5 ml of dry pyridine was added 651 mg of 1,3-dicyclohexylcarbodiimide, and the mixture was stirred for 10 hours at room temperature. The precipitates were filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in 20 ml of a 1N-hydrochloric acid, acidic solution was washed twice with 25 ml of diethyl ether. A 2N-aqueous sodium hydroxide was added to the solution to a pH of 11. A separated oil was extracted with 50 ml of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 525 mg of cyclohexylmethyl 2-pyridylacetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17](Cl)=[N:16][C:15]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]2[S:21][C:20]3[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:18][C:17]([N:32]4[C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=[C:31]4[CH2:29][CH3:30])=[N:16][C:15]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(C=C3CN(C(=O)OC(C)(C)C)C3)cc2n1
Temperature: 110 °C
Yield: 112.2 %

Procedure:
A mixture of 3-(2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethylene)azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.51 mmol), 2-ethylbenzimidazole (400 mg, 2.74 mmol), tris(dibenzylideneacetone)dipalladium (115 mg, 0.13 mmol), XPhos (240 mg, 0.50 mmol) and Cs2CO3 (1.25 g, 3.84 mmol) in dioxane (25 mL) was purged with argon then heated at 110° C. for 16 h. The reaction mixture was filtered through Celite®, washing with DCM, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording the title compound as an orange solid (1.5 g, quant.). LCMS (method A): RT 3.40 min [M+H]+ 533.4
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](I)=[C:16]([CH3:19])[N:15]=[C:14]2[CH3:20])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.N.ClCCl.[CH3:25][N:26]1CCCC1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([C:25]#[N:26])=[C:16]([CH3:19])[N:15]=[C:14]2[CH3:20])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1I
Reactant: CN1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: ClCCl
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1C#N
Reaction time: 3 h

Procedure:
A mixture of 8-methyl-6-(2,4-dimethyl-5-iodoimidazol-1-yl)-2-(1H)-quinolone (0.1 g), cuprous cyanide (0.047 g) and palladium acetate (0.01 g), in N-methyl-2-pyrrolidone (1 cm3) was heated and stirred at 175° for 3 hours. The cooled mixture was poured into aqueous ammonia solution (10 cm3 ; S.G. 0.880) and dichloromethane (50 cm3) and the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined and dried (MgSO4) organic extracts were filtered and evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of appropriate fractions afforded an oil which crystallised on trituration with ether to give the title compound, m.p. 334°-337° (0.03 g).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]3[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:26]=2)=[N:6][N:5]=1)=[N+]=[N-]>CO.C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[C:12]3[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[N:26]=2)=[N:6][N:5]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N=[N+]=[N-])s3)ccc21
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N)s3)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl 5-(5-azido-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (224 mg, 0.444 mmol) in MeOH/THF (5 mL, 3:2) was added Lindlar catalyst (59.2 mg, 0.222 mmol). The mixture was stirred at RT under hydrogen for 15 h, then filtered through a plug of celite and washed with DCM/MeOH. The filtrated was concentrated to give the crude material. MS (ESI, pos. ion) m/z: 479 (M+1).