Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[N:10]1)[CH3:8])(=O)=O.[OH-].[K+]>CO.O1CCCC1>[OH:5][CH:6]([CH3:35])[CH:7]([N:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH:11]=[N:10]1)[CH3:8]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(C)(=O)=O)c4=O)cc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
According to the precedure described in Nakamura et al. (J.A.C.S. 1985, 107 p2138), intermediate 5d (0.001 mol) was added to a solution of KOH (0.03 g) in CH3OH (7 ml) and tetrahydrofuran (3 ml). The mixture was stirred at 100° C. for 4 hours, yielding [S-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 5c).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]1[C:9](Cl)=[O:10].N1C=CC(C)=CC=1.[CH2:20]([C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[CH:29]([OH:32])[CH:30]=[CH2:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[CH2:20]([C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[CH:29]([O:32][C:9]([CH:3]1[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[C:2]1([CH3:12])[CH3:1])=[O:10])[CH:30]=[CH2:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: C=CC(O)c1ccccc1Cc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccncc1
Product: C=CC(OC(=O)C1C(C=C(Cl)Cl)C1(C)C)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
91 g (0.04 mole) of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid chloride are added dropwise, whilst stirring, to 4.6 g (0.05 mole) of γ-picoline, 100 ml of absolute ether and 8.5 g (0.38 mole) of 2-benzyl-(α-vinyl)-benzyl alcohol at 0°-5° C. After having been stirred for 12 hours at 25° C., the reaction mixture is filtered and the filtrate is successively washed with 2 N sodium bicarbonate solution, 2 N hydrochloric acid and water. After drying over sodium sulfate, the filtrate is concentrated under reduced pressure and the resulting oil is purified by column chromatography over silica gel, using toluene as the eluant.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C@H:40]([CH3:43])[CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[I:25][CH2:41][C@H:40]([CH:37]1[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:35][CH2:36]1)[CH3:43]
Reactant: C[C@H](CO)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CI)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 1.57 g (6.0 mmol) of triphenylphosphine and 0.41 g (6.0 mmol) of imidazole in 40 mL of CH2Cl2 was treated with 1.52 g (6.0 mmol) of iodine and stirred at rt for 30 min. A solution of 1.15 g (4.7 mmol) of 2-(S)-((t-butoxycarbonyl)piperidin-4-yl)propanol (from EXAMPLE 30, Step D) in 10 mL of CH2Cl2 was added and the resulting mixture was stirred at rt for 20 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of sat'd NaHCO3, 100 mL of 5% Na2SO3, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 60 g of silica gel using 10:1 v/v hexanes/ether as the eluant afforded 1.57 g (95%) of the title compound: 1H NMR (500 MHz) δ 0.98 (d, J=6.5, 3H), 1.10-1.20 (m, 2H), 1.26-1.36 (m, 1H), 1.40-1.50 (m, 1H), 1.45 (s, 9H), 1.64 (app d, J=11.0, 11H), 2.67 (br s, 2H), 3.19-3.28 (m, 2H), 4.13 (br s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
A solution of indole-5-carboxylic acid (68.3 g), benzyl alcohol (64.9 g) and triphenylphosphine (157.0 g) in tetrahydrofuran (1.2 L) was cooled to 5° C. and treated dropwise with diethyl azodicarboxylate (90.0 g). Upon completion of the addition, the mixture was allowed to warm to room temperature. The reaction was stirred for 24 hours and then evaporated. The residue was taken up in diethyl ether (1 L) and filtered. The filtrate was evaporated to give a yellow syrup which was purified by flash chromatography, eluting sequentially with 2:1, 1:1 and 1:2 hexane:methylene chloride, to afford a yellow-white solid. This material was triturated with 1:1 hexane: methylene chloride (300 mL) and filtered to give benzyl indole-5-carboxylate as a white solid (74.2 g, 70%); mp 127°-129 ° C.; partial NMR (300 MHz, CDCl3): 5.39 (s, 2H, CH2), 6.61 (m, 1H, indole-H(2)), 8.56 (br, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Reactant: c1nnn[nH]1
Product: CC1c2c(ccn2-c2nnn[nH]2)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][C:3]=1[CH3:11]>CC(O)=O.[Zn]>[CH3:11][C:3]1[CH:4]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[S:6][CH:2]=1
Reactant: Cc1cc(S(N)(=O)=O)sc1Br
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1csc(S(N)(=O)=O)c1
Reaction time: 8 h
Yield: 42 %

Procedure:
To a stirred solution of 5-bromo-4-methylthiophene-2-sulfonamide (3.1 g, 12.1 mmol) in AcOH (30 mL) is added zinc dust (2.4 g, 36.2 mmol). The reaction mixture is heated to reflux for 8 hr. After 8 hr, the reaction mixture is cooled and filtered. The filtrate is neutralized with 1 M NaOH. The aqueous layer is extracted with EtOAc (300 mL). The organics are dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with CH2Cl2 to afford the title compound (0.90 g, 43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O)[CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:35]([O:41]CC)(=O)[CH2:36][C:37]([CH3:39])=O>C(O)(=O)C>[CH3:1][C:2]1([CH3:27])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]3[C:35](=[O:41])[CH2:36][C:37]([CH3:39])=[N:12]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Temperature: 100 °C
Yield: 57.5 %

Procedure:
Di-tert-butyl 1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 4b (2.70 g, 7.18 mmol) was dissolved in 100 mL of acetic acid followed by addition of 20 mL of trifluoroacetic acid. After the mixture was reacted at room temperature for 2 hours, ethyl acetoacetate (0.98 g, 7.54 mmol) was added. Then the mixture was heated to 100° C. and reacted for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to remove acetic acid. The reaction mixture was neutralized by saturated sodium bicarbonate solution, and then was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 4c (1.0 g, yield 47.7%) as a light brown solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([CH2:35][CH2:36][OH:37])[CH2:7]1)=[O:5])C.Cl>O1CCOCC1>[OH:37][CH2:36][CH2:35][N:8]1[CH2:9][CH2:10][CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1CN(CCO)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(CCO)CC3C(=O)O)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
To a solution of 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (0.6 g, 1.14 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (10 mL). The reaction was heated to 60° C. for 19 h and the solvent was then removed in vacuo. The residue was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting with an acetonitrile:water gradient to afford 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.4 g, 71.4%). MS: 500 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][N:6]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C@H:24]([OH:37])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:26]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.O.[OH-].[Li+].C(O)(=O)C>C(O)C.O>[CH:39]1([CH2:38][N:6]([CH2:5][C:4]([OH:42])=[O:3])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][CH:19]([NH:22][CH2:23][C@H:24]([OH:37])[C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([NH:32][S:33]([CH3:36])(=[O:34])=[O:35])[CH:26]=4)[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:41][CH2:40]1
Reactant: CCOC(=O)CN(CC1CC1)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N(CC(=O)O)CC4CC4)cc3)CC2)ccc1O
Reaction time: 0.33 h

Procedure:
To a stirred solution of 0.15 9 (0.24 mmol) of [cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic acid ethyl ester ( ) in 2 mL of ethanol, 0.1 g (2.4 mmol) of lithium hydroxide monohydrate in 2 ml of water was added dropwise over 10 minutes. After 20 minutes, the reaction mixture was quenched with .13 ml (2.4 mmol) of glacial acetic acid. The solvent was removed in vacuo and the pink aqueous residue was pipetted out of the flask. The solid was then washed with water and ethyl acetate and then dried via vacuum line to give 0.134 g of the title compound as a tan solid; 1H NMR (DMSO) δ 0.82 (m, 1H), 1.41 (m, 2H), 1.85-1.97 (m, 2H), 2.68-2.82 (m, 8H), 2.92 (s, 3H), 3.04 (d, J=6.84 Hz, 2H), 3.30 (m, 5H), 3.76 (m, 4H), 4.58 (m, 1H), 6.83 (d, J=8.25 Hz, 1H), 6.94-7.05 (m, 3H), 7.18 (d, J=1.86 Hz, 1H), 7.60 (d, J=8.88 Hz, 2H); MS (ES) m/z 597.1 (MH+); HRMS (MH−) for C26H36N4O8S2: 595.1904.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[CH:20]=[CH:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>C(O)CC(C)C>[CH3:17][C:18]1[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=1[CH:20]=[CH:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: Cc1ccccc1C=CC(=O)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccccc4C)CC3)nc(N)c2cc1OC

Procedure:
A mixture of 479 mg. of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 461 mg. of 2-methylcinnamoylpiperazine in 10 ml. of isoamyl alcohol was heated under reflux for 4 hours. After ice-cooling, the reaction mixture was filtered and the product thus obtained was washed with ethanol to yield 812 mg. of the desired product as the hydrochloride.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:20]=1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 388.11 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[CH2:13]([C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]=[CH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Brc1cccc(N2CC=CC2)c1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: C1=CCN(c2cccc(Cc3ccccc3)c2)C1
Reaction time: 8 h

Procedure:
To a mixture of 6.6 g of 1-(3-bromophenyl)-2,5-dihydropyrrole, 800 mg of 1,3-bis(diphenylphosphino)propanenickel (II) chloride and 40 ml of tetrahydrofuran was added dropwise 22 ml of a 2.0 M tetrahydrofuran solution of benzyl magnesium chloride, followed by stirring overnight as it was. The reaction mixture was separated with a saturated aqueous ammonium chloride solution-ethyl acetate, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography with 1% ethyl acetate/hexane, to give 2.1 g of the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60]OS(C)(=O)=O)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42].CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([C:43]2[CH:44]=[C:45]([CH2:60][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:46](=[O:59])[N:47]([CH2:49][CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[N:48]=2)[CH:38]=[CH:39][C:40]=1[O:41][CH3:42]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CCCc3ccc(F)cc3)n2)cc1F
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 (10), 6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 79.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.O1CCCCC1[N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C@@H:31]([NH2:33])[CH3:32])=[CH:30][C:25]=2[N:24]=[CH:23]1>CCCCO>[NH:22]1[C:26]2[CH:27]=[CH:28][C:29]([C@@H:31]([NH:33][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=4)[CH:5]=[CH:4][N:3]=3)[CH3:32])=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: C[C@H](N)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(Nc2ccnc(N[C@@H](C)c3ccc4[nH]cnc4c3)n2)n[nH]1

Procedure:
To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (105 mg, 0.5 mmol) in n-BuOH (2 mL) in a microwave vial was added 126 (184 mg, 0.75 mmol). To the solution was added dropwise TEA (0.21 mL, 1.5 mmol) and the vial sealed and irradiated in a in the microwave synthesizer at 110° C. for 6 h. The solvent was evaporated under reduced pressure and the crude residue was taken up in DCM (5 mL) and MeOH (5 mL) and the solvent was again concentrated in vacuo. The residue was diluted in DMF (1 mL) and filtered. The crude mixture was purified by reverse phase HPLC to afford 9 mg (5%) of I-121.
Reaction SMILES: [CH2:1]([N:3](C(OC(C)(C)C)=O)[CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]/[CH:9]=[CH:10]/[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25][CH3:26])C(OC(C)(C)C)=O)[CH3:2].[ClH:48]>C(OCC)C>[ClH:48].[ClH:48].[ClH:48].[ClH:48].[CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCCN(CCCN(C/C=C/CN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CCCNCCCNC/C=C/CNCCCNCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 0.5 g (0.745 mmol) of (E)-1-ethyl-14-propyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene and 10 ml of 3N methanolic hydrochloric acid is stirred for 15 h at room temperature, and then 20 ml of diethyl ether are added. Working up analogously to Example 1 yields the title compound, m.p. >260° C. 1H-NMR (D2O): δ0.96(t,3H); 1.28(t,3H); 1.63-1.76(m,2H); 2.05-2.16(m,4H); 2.97-3.18(m,12H); 3.77(d,4H); 6.05-6.07(m,2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[C:28](O)(=[O:30])[CH3:29]>>[F:3][C:4]1[C:12]2[O:11][CH:10]=[CH:9][C:8]=2[C:7]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:28](=[O:30])[CH3:29])[CH2:25][CH2:26]3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3ccc(F)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (60 mg, 62%), MS (ISP) m/z=387.3 [(M+H)+], mp 203.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(7-fluoro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate C) (104 mg, 0.25 mmol) and acetic acid.
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[NH:26])=[CH:20][CH:19]=1.[K+].[Br-]>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:26]=[C:25]2[C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(C(=N)Nc2ccc(F)cc2)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1c(SC)nc(-c2ccc(SC)cc2)n(-c2ccc(F)cc2)c1=O
Yield: 15.7 %

Procedure:
The title compound was prepared from diethyl [bis(methylthio)methylene]malonate (0.88 g, 3.3 mmol) and N-(4-fluorophenyl)-4-(methylthio)benzenecarboximidamide (0.87 g, 3.3 mmol) (prepared according to the procedure described in preparation 5) by following the procedure described in example 41 (0.22 g, yield 15.7%, mp 151-155° C., purity 99.72% by HPLC). 1H-NMR (CDCl3):δ 1.37-1.40 (t, 3H), 2.45 (s, 3H), 2.55 (s, 3H), 4.38-4.43 (q, 2H), 7.02-7.07 (m, 4H), 7.11-7.14 (m, 2H), 7.22-7.26 (m, 2H). IR (KBr) cm−1: 3360, 3072, 2978, 2924, 1694 (—C═O). MS m/z:431.2 (M+).
Reaction SMILES: C(N[C:15]1[CH:46]=[CH:45][C:18]([C:19]([C:21](S)(C2N(C3C=CC(O)=CC=3)N=NN=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[O:23])=[O:20])=[CH:17][CH:16]=1)(=O)CCCCCCCCCCC.OC1C=CC(N2C(S)=NN=N2)=CC=1.S(Cl)([Cl:63])(=O)=O>C(O)C>[Cl:63][C:45]1[CH:46]=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]([CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])=[O:20]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCCCCCCCC(=O)Nc1ccc(C(=O)C(S)(C(=O)Nc2ccccc2Cl)c2nnnn2-c2ccc(O)cc2)cc1
Agent: Oc1ccc(-n2nnnc2S)cc1
Solvent: CCO
Product: O=C(CC(=O)c1ccccc1Cl)Nc1ccccc1

Procedure:
2-(p-lauroylaminobenzoyl)-2-(1-p-hydroxy-phenyltetrazole-5-yl)-mercapto-(o-chloro)-acetanilide (Compound 2) Analogously to Synthesis Example 1, 4.32 g. (0.02 mol) Na-salt of 1-(p-hydroxyphenyl)-5-mercaptotetrazole are reacted with 10.12 g (0.02 mol) 2-chloro-2-(p-lauroylamino)-benzoyl-(o-chloro)-acetanilide. An an intermediate product the respective 2-chlorobenzoylacetanilide was prepared according to the method "chlorination with sulfurylchloride in methylene" analogously to Synthesis Example 2. yield=7.2 g. (1×ethanol)=76% of theoretical; melting point 142° C.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br-].[In+3].[Br-].[Br-].C(Cl)Cl.[Br:14][C:15]1[CH:16]=[C:17]2[C:23]([CH:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=3[Cl:34])O)=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1>>[Br:14][C:15]1[CH:16]=[C:17]2[C:23]([CH:24]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=3[Cl:34])[C:5]#[N:6])=[CH:22][NH:21][C:18]2=[N:19][CH:20]=1
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: C[Si](C)(C)C#N
Agent: [Br-]
Agent: [In+3]
Solvent: ClCCl
Product: N#CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of trimethylsilyl cyanide (0.51 mL, 3.8 mmol) and indium(III) bromide (34.1 mg, 0.0961 mmol) in DCM (5.00 mL, 78.0 mmol) was added (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol (150.0 mg, 0.3846 mmol). The resulting mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/Hexane 1:1 as eluent). 1H NMR (400 MHz, CD3OD): δ=6.52 (s, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.45 (t, J=8.7 Hz, 1H), 7.63 (dd, J=9.1, 4.8 Hz, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.3 Hz, 1H). MS (ES+): m/z 397.85, 399.88, 401.85 [MH+]. HPLC: tR=4.19 min (OpenLynx, polar—5 min).
Reaction SMILES: P([O:4][PH:5]([OH:7])=[O:6])(O)=O.C([C:11]([CH:18]([CH3:20])C)([CH:15]([CH3:17])C)C(C)C)(C)C.BrCCC(Br)C>>[CH3:17][CH:15]1[CH2:11][CH2:18][C:20]1([P:5]([OH:4])(=[O:6])[OH:7])[P:5]([OH:7])(=[O:4])[OH:6]
Reactant: CC(C)C(C(C)C)(C(C)C)C(C)C
Reactant: O=[PH](O)O[PH](=O)O
Agent: CC(Br)CCBr
Product: CC1CCC1(P(=O)(O)O)P(=O)(O)O

Procedure:
Using the procedure of Example I, tetraisopropyl methane diphosphonate was converted to tetraisopropyl 2-methyl cyclobutane-1,1 diphosphonate by reaction with 1,3 dibromobutane at 80° C. for 4 hours. 31P NMR (CDCl3) chemical shift 24.1 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:3]2[N:2]([CH3:1])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[N:4]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2nc3ccccc3n2C)cc1OC
Yield: 92.6 %

Procedure:
1-Methyl-2-formylbenzimidazole (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (221 mg) through Method A (production step 2), to thereby yield the target product (yield: 369 mg, 93%).