Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32](C4C=CC([N+]([O-])=O)=CC=4)[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: Clc1ncccn1
Product: COc1ccc(C2=NN(C3CCN(c4ncccn4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 2-Chloro-pyrimidine and starting compound A1 as described for compound 11. Crystallisation from methanol. M. p. 163-166° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Fc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2-methylimidazole (13.6 g, 165 mmol) in DMF (500 ml) was added sodium hydride (6.60 g, 165 mmol, 60% dispersion in mineral oil) in portions. The resulting white suspension was stirred at room temperature for 30 min, 4-fluoroiodobenzene (33.3 g, 150 mmol) added and the mixture heated at 100° C. After 16 hr, the bulk of DMF was removed by evaporation. The residue was then partitioned between a mixture of ethyl acetate-toluene (2:1, 500 ml) and water(250 ml). The organic layer was separated and washed with water (250 ml). Product was extracted with 10% aqueous hydrogen chloride (2×200 ml) and the combined aqueous extracts neutralized with 30% aqueous potassium hydroxide. The resulting suspension was extracted with a mixture of ethyl acetate-toluene (2:1, 3×250 ml) and the combined organic extracts washed with water (2×250 ml), brine (250 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was recrystallized from toluene to afford the titled compound as off-white solids (21.9 g, 51%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]C1C=CC(C(O[C@H](C)CCCCCC)=O)=CC=1F>CN(C)C1C=CN=CC=1.ClCCl>[C:8]([NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:16]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(O)c(F)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N,N′-Dicyclohexylcarbodiimide (0.64 g, 3.1 mmol) and 4-(dimethylamino)pyridine (0.10 g, 0.1 mmol) was added to a stirred solution of compound 42 (1.23 g, 3.1 mmol) and compound 15 (0.83 g, 3.1 mmol) in dichloromethane. The reaction mixture was left stirring at room temperature for 72 h until completion of the reaction. Tile dicyclohexylurea formed was filtered off and the solvent removed in vacuo to yield a viscous colourless oil which was purified by column chromatography (ethyl acetate) on silica. The colourless material was then heated in ethanol and cooled to −60°, filtered off and dried in vacuo (P2O5). Yield 1.83 g (91%), [α]D=−22.35° at 24° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH2:28])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2([NH:28][CH2:16][CH2:15][C:2]3([OH:1])[CH2:3][CH2:4][C:5]4([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]4)[CH2:13][CH2:14]3)[CH2:26][CH2:27]2)=[CH:23][CH:24]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: NC1(c2ccc(Br)cc2)CC1
Product: CC1(C)COC2(CCC(O)(CCNC3(c4ccc(Br)cc4)CC3)CC2)OC1
Yield: 42 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and 1-(4-bromo-phenyl)-cyclopropylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 42% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=438/440 (Br) [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27](OS(C)(=O)=O)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:7])[CH2:3][CH2:2]1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:34])[CH:10]2[NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1)N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g) in benzene (11 ml) is added morpholine (0.26 ml) under ice cooling, and the mixture is kept at 10° C. overnight. The reaction mixture is washed with water, dried, and evaporated under reduced pressure. Purification of the obtained residue (1 g) by chromatography over silica gel (10 g) using a mixture of benzene and ethyl acetate (1:2) gives p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido- 2-oxoazetidin-1-yl]-α-(1-morpholinoethylidene)acetate (602 mg). Foam.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:24])[CH:22]=[CH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C=CC(=O)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 12 h

Procedure:
A solution of dicyclohexylamine (19.92 ml, 0.10 mole) and triethylamine (27.88 ml, 0.20 mole) in ethyl ether (100 ml) was cooled to 0° C. A solution of acryloyl chloride (7.93 ml, 0.1 mole) in ethyl ether (20 ml) was added and the solution was stirred for 12 hours, filtered and concentrated to obtain the product as a solid which was dried in vacuo. The stucture was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O-])(=O)C.[NH4+].C([O-])(=O)C.[Na+].C([BH3-])#[N:26].[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:26])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CC(C)N)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To 2 g (10.29 mmol) of 3,4-dimethoxyphenyl acetone was added 10 mL of methanol, 7.9 g (102 mmol) of ammonium acetate, 844 mg (10.2 mmol) of sodium acetate and 970 mg (15.4 mmol) of sodium cyanoborohydride. The pH of the reaction was adjusted to between 6-7 by addition of glacial acetic acid. The reaction mixture was allowed to stir at room temperature 18 hours and concentrated under reduced pressure. To the residue 100 mL of water was added, and the pH of the reaction was adjusted to 14 using 6 N NaOH. The aqueous layer was extracted with 6×30 mL of chloroform. Organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure to give 2 g (10.24 mmol, 99%) of 3A as a light yellow gum (M+H 196).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.[CH3:22][NH2:23]>C1(C)C=CC=CC=1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH3:22])[C:3]=2[N:10]=[N:9]1
Reactant: Fc1ccccc1Cn1nnc2c(Cl)ncnc21
Reactant: CN
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNc1ncnc2c1nnn2Cc1ccccc1F
Reaction time: 15 h

Procedure:
A solution of 9.22 g (35 mmol) of crude 7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine in 150 ml of toluene is added dropwise, while stirring, to a mixture of 750 ml of ethanol and 200 ml of 40% aqueous methylamine solution. The whole is left to stand for 15 hours at room temperature and then the solvent is distilled off under reduced pressure. 500 ml of water are added to the residue. The precipitated product is filtered off with suction and recrystallised from methanol. In this manner 3-(2-fluorobenzyl)-7-(N-methylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 180°-182° is obtained.
Reaction SMILES: C(OP([CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH3:11])(=O)OCC)C.[CH2:18]([O:20][C:21]([C@H:23]1[C@H:25]([CH:26]=O)[C:24]1([CH3:29])[CH3:28])=[O:22])[CH3:19].O>O1CCCC1>[CH2:18]([O:20][C:21]([CH:23]1[CH:25]([CH:26]=[C:9]([CH2:10][CH3:11])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]1([CH3:28])[CH3:29])=[O:22])[CH3:19]
Reactant: CCOP(=O)(OCC)C(CC)c1ccccc1
Reactant: CCOC(=O)[C@H]1[C@H](C=O)C1(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1C(C=C(CC)c2ccccc2)C1(C)C
Reaction time: 6 h
Yield: 52 %

Procedure:
51.2 g (0.2 mol) of 1-phenylpropyl-phosphonic acid diethyl ester, dissolved in 30 ml of anhydrous tetrahydrofuran, were added dropwise to a mixture of 24 g (0.214 mol) of potassium tert.-butylate and 300 ml of anhydrous tetrahydrofuran at 20°-25° C., while stirring. After the mixture had been subsequently stirred at 20°-25° C. for a further 2 hours, 34 g (0.2 mol) of cis/trans-2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 25° C., while stirring. Stirring was then continued at 60° C. for a further 6 hours. 500 ml of water were then added and the reaction mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 28.3 g (52% of theory) of 2,2-dimethyl-3-(2-ethyl-2-phenyl-vinyl)cyclopropanecarboxylic acid ethyl ester (isomer mixture) were obtained as a yellow oil with a boiling point of 142°-150° C./2 mbar.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([CH2:11][CH2:12][NH2:13])[N:10]=1)[CH2:3][CH2:4][CH3:5].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=O.C(O)C>C(Cl)(Cl)Cl>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2[CH:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])[NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Yield: 44.1 %

Procedure:
A mixture of 2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole hydrochloride (0.278 g), ethyl glyoxylate (0.179 g) and ethanol (5 ml) is refluxed for three days. To the mixture is added chloroform, and the mixture is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=10:1) to give ethyl 2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.136 g) as a foam.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(N)cc2O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanesulfonyl chloride (55 μL) and pyridine (85 μL) were added dropwise to a solution of 4-(4-chlorophenyl)-2.2-dimethyl-2H-1,3-benzoxazin-7-ylamine (a compound of Reference Example 1, 101 mg) in chloroform (8 mL) and said mixture was stirred at room temperature for 2 days. The reaction solution was purified by column chromatography on silica gel (Chromatorex NH-silica gel, FUJI SILYSIA CHEMICAL LTD., Solvent: chloroform/methanol=100/0 to 90/10) and the obtained powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (112 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CC=CC=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1Oc1ccccc1
Temperature: 145 °C
Yield: 12 %

Procedure:
6.0 g of 4-hydroxy-3-methoxybenzaldehyde, 75 ml of pyridine, 12.0 g of iodobenzene, 10.9 g of potassium carbonate and 6.24 g of cupric oxide were mixed and heated at 145° C. for 18 hours in a sealed tube. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and subjected to celite filtration. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 1.11 g (yield: 12%) of the above identified compound as a colorless oily substance.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]1[O:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[NH3:15]>CO>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[O:6][C@@H:4]2[C:3]([NH2:15])=[O:2])=[CH:8][CH:9]=1
Reactant: N
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Solvent: CO
Product: Cc1ccc([C@H]2O[C@@H]2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a mixture of (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionic acid methyl ester (3.84 g) and methanol (25 ml) is added dropwise a solution of 28% aqueous ammonia (6.1 g) in methanol (10 ml) under ice-cooling. The reaction mixture is gradually warmed to room temperature, and stirred for two hours, and further stirred for one hour under ice-cooling. The precipitated crystals are collected by filtration, washed, and dried at 50° C. to give (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionamide (2.71 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=1)#[CH:11]>C(NC(C)C)(C)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:13][C:14]=1[CH3:19]
Reactant: C#Cc1ccc(F)c(C)c1
Reactant: COc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: COc1cncc(C#Cc2ccc(F)c(C)c2)c1
Temperature: 60 °C
Yield: 51.1 %

Procedure:
Dissolve 3-bromo-5-methoxypyridine (1.0 g, 5.35 mmol) in diisopropylamine (17 mL) and toluene (10 mL) under nitrogen. Add tetrakis(triphenylphosphine)palladium (0.200 g, 0.16 mmol). Heat at 60° C. and add 4-ethynyl-1-fluoro-2-methylbenzene (717 mg, 5.35 mmol) and copper (I) iodide (20 mg, 0.11 mmol). After 20 h add additional 4-ethynyl-1-fluoro-2-methylbenzene (100 mg, 0.75 mmol) and heat at 60° C. for 5 h. Concentrate and purify using silica gel chromatography, eluting with 30:70 to 40:60 ethyl acetate:hexanes, to give the title compound (660 mg, 51%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]([CH3:20])[CH2:9][N:10]2[CH:14]([CH2:15][C:16](OC)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[CH3:21][NH2:22]>>[CH3:21][NH:22][C:16](=[O:17])[CH2:15][CH:14]1[CH2:13][S:12][C:11]2=[C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH:8]([CH3:20])[CH2:9][N:10]12
Reactant: COC(=O)CC1CSC2=C(C(=O)OC(C)C)C(C)CN21
Reactant: CN
Product: CNC(=O)CC1CSC2=C(C(=O)OC(C)C)C(C)CN21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4.5 g of methyl (7-isopropoxycarbonyl-6-methyl-2,3,5,6- tetrahydropyrrolo[2,1-b]thiazol-3-yl-)acetate was added 100 ml of a 40% aqueous solution of monomethylamine. The mixture was stirred at room temperature for 20 hours. After distilling off the monomethylamine, the residue was extracted with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, 4.1 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:20][CH2:21][O:22][CH3:23])[N:3]=1
Reactant: Oc1cccc2nc(Cl)ccc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cccc2nc(Cl)ccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
2-Chloro-quinolin-5-ol (CAS 124467-35-2) (0.3 g, 1.56 mmol) was dissolved in acetone (10 mL) and potassium carbonate (0.368 g, 2.75 mmol) was added. After addition of 2-bromethylmethylether (0.25 ml, 2.7 mmol) the reaction mixture was stirred for 18 h at 50° C. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated. The residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1/4:1) to yield 2-chloro-5-(2-methoxy-ethoxy)-quinoline as a colourless oil (0.12 g, 30%). MS: m/e=238.8 (M+H+)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1.[H-].[Na+]>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:33]#[N:34])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(CC#N)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CCCCCCc2ccccc2)c1
Yield: 54.1 %

Procedure:
By working in a way similar to that described in example 2 but using toluen-4-sulphonic acid 6-phenyl-hexyl ester (5.4 g, 16.24 mmoles), obtained as described in example 11, 3-methoxy-phenyl-acetonitrile (2.39 g, 16.24 mmoles), NaH (55-65%, 715 mg, 17.86 mmoles) and DMF (25 ml), 2.7 g of the title compound were obtained (yield: 54.1%).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([CH3:16])[CH:6]=1)C.[CH2:17]=[CH:18][CH:19]=[CH2:20]>C1(C)C=CC=CC=1>[CH3:16][C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:20][CH2:19][CH:18]=[CH:17][CH2:4]2)[CH:6]=1
Reactant: Cc1cc(CN(C)C)cc(C(C)(C)C)c1O
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CC1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2

Procedure:
Following the same general procedure as in Example I, 40 mmols of N,N-dimethyl-4-aminomethyl-2-methyl-6-t-butylphenol were reacted with 80 mmols of 1,3-butadiene in 81 g of toluene at about 207° C. for 10 hours. The uncorrected isolated yield of 2-methyl-4-t-butylspiro[5.5]undeca-1,4,8-trien-3-one was 83%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([NH2:20])=[CH:18][N:17]=[C:16]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:15]=23)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A mixture of racemic trans [3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester (23.7 g, 47.2 mmol) and palladium hydroxide (2.44 g, 20%) in acetic acid (285 mL) was stirred under an atmosphere of hydrogen at 50° C. for 3 hours and then room temperature for 18 hours. The mixture was filtered through Celite® and then concentrated in vacuo. The residue was dissolved in DCM, then washed (saturated sodium hydrogen carbonate solution (3×) and brine) and concentrated to dryness. Purification by column chromatography on silica gel (gradient: DCM to ethyl acetate) afforded 11.6 g (52%) of racemic trans [3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a purple solid. LCMS (Method B, ESI): RT=2.85 min, m+H=472.4; 1H NMR (400 MHz, DMSO) δ: 8.00 (d, 2H), 7.66 (t, 1H), 7.57 (t, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 6.97 (d, 1H), 6.82 (d, 1H), 5.21 (d, 1H), 4.35 (m, 3H), 3.95 (m, 1H), 2.13-1.91 (m, 2H), 1.79 (m, 2H), 1.44 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[C:14]=1[N:15]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[N:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ncnc2c1nc(-c1ccccc1Cl)n2-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reaction time: 23 h

Procedure:
9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-ol I-(4A-7)b (2.49 g, 6.97 mmol) was suspended in 50 ml of toluene. Triethylamine (1.07 ml, 7.68 mmol) was added followed by addition of POCl3 (720 μl, 7.72 mmol) at room temperature. The reaction was warmed to reflux and stirred for 23 hours to give a clear orange solution. After cooling the reaction to room temperature it was concentrated under reduced pressure, diluted with isopropanol (50 ml) and then concentrated further under reduced pressure until copious amount of precipitate came out of solution. The concentrated suspension was cooled in an ice bath and stirred for 2 hours. The precipitate was collected on a sintered glass funnel and rinsed with cold isopropanol to afford, after drying in vacuo, I-(4A-7)c as an off-white solid (2.13 g, 82%): +ESI MS (M+1) 375.1; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.76 (dd, J=7.46, 1.2 Hz, 1H), 7.58–7.40 (m, 7H).