Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([O:12]C(=O)C)[C:6]=1[Cl:16])(=[O:3])[CH3:2].[OH-].[Li+].Cl>O.O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([OH:12])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(I)cc(OC(C)=O)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Oc1cc(I)cc(O)c1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 107.7 %

Procedure:
A mixture of 2-chloro-5-iodo-1,3-phenylene diacetate (5) (5.16 g, 14.5 mmol) and 1M lithium hydroxide (29.1 mL, 29.1 mmol) in H2O (5 mL) and dioxane (20 mL) was stirred at 60° C. for 4 h then at RT for 20 h. The reaction mixture was acidified by the addition of 1M HCl and the product was extracted with EtOAc (150 mL). The organic solution was dried over MgSO4 and the solvent was removed in vacuo. The resulting oil was slurried with 1:1 DCM: isohexanes and the solvents were removed in vacuo to yield 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (4.88 g, 86%) as a brown solid: m/z 311 [M−H]− (ES−).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:12])=[O:11])([O-:3])=[O:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O.C(OC(C)C)(C)C>[CH3:27][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(C)OC(C)C
Product: CN(CCCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of tert-butyl 5-(2-nitrophenylsulfonamido)pentylcarbamate 30c (32.61 g, 84 mmoles) and potassium carbonate (13.96 g, 1.2 eq) in acetone (300 mL) was added methyl iodide (5.5 mL, 1.05 eq). After stirring at RT overnight, more methyl iodide (1 eq) and potassium carbonate (0.6 eq) was added and the RM was stirred at RT until completion. The RM was then diluted with water and extracted with DCM. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 31.59 g (93% yield) of tert-butyl 5-(N-methyl-2-nitrophenylsulfonamido)pentylcarbamate 30d as a white solid; m/z 402 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[S:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][OH:24])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccccc1SCCCCCCSc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccccc1SCCCCCCSc1ccccc1

Procedure:
To a suspension of lithium aluminum hydride (0.292 g, 0.007 mole) in tetrahydrofuran (30 ml) is added a solution of 2-(6-thiophenoxyhexylthio)benzoic acid (2.42 g, 0.007 mole) in tetrahydrofuran (30 ml). The reaction is conducted as in Example 1b).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][C:18]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[C:25]2[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=2)[N:19]=1.O>CN(C)C=O>[C:10]1([N:9]([CH2:17][C:18]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=3)[C:25]3[C:20](=[CH:21][C:22]([O:40][CH3:41])=[C:23]([O:38][CH3:39])[CH:24]=3)[N:19]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CN(c3ccccc3)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.9 %

Procedure:
Sodium hydride (oily, 60%, 0.129 g) was added to a solution of diphenylamine (0.497 g) in N,N-dimethylformamide (10 ml), and the mixture was stirred at room temperature for 20 minutes. Then, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (1.0 g) was added, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate - hexane (1:1, v/v) gave 2-(N,N-diphenylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.27 g, 20%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 215°-216° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.Cl[C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1.[H-].[Na+]>CN(C=O)C>[Br:8][C:7]1[C:2]([NH:1][C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Cc1cnc(N)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2nc(C)cc(C)n2)c(Br)c1

Procedure:
Part A: A 1.0 gram (5.35 mmol) portion of commercially available 2 -amino-3-bromo-5-methylpyridine was coupled to 2-chloro-4,6-dimethylpyrimidine (Example 1, part A) using NaH (1.2 eq) in DMF to give N-[3-bromo-5-methyl-pyridin-2-yl]-4,6-dimethyl-2-pyrimidinamine. C12H13N4Br MS 293 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10].Br[CH2:16][CH2:17][OH:18]>CN(C=O)C.C(OCC)(=O)C>[Cl:3][C:4]1[CH:11]=[C:8]([CH:7]=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH2:16][CH2:17][OH:18])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc(Cl)c1OCCO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.24 g, 6.00 mmol) in DMF (8 mL) was added a solution of 5-chlorovanillin (0.746 g, 4.00 mmol) in DMF (2 mL). The reaction mixture was stirred at RT for 20 minutes and 2-bromoethanol (0.42 mL, 5.93 mmol) added. The reaction mixture was heated at 50° C. for 90 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0-50% ethyl acetate in iso-hexane to afford the title compound (0.413 g, 48%).
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C@H:20]1[C@H:25]([NH:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([NH:39][C:40]3[N:45]=[C:44]([N:46](CC)[CH2:47][C:48]4C=CC(OC)=CC=4)[C:43]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:42]4[N:41]=3)[C:32]=2[Cl:63])[CH2:21]1)=[O:18])([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>ClCCCl>[P:6]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C@H:20]1[C@H:25]([NH:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[C:35]([C:37]#[N:38])[CH:34]=[C:33]([NH:39][C:40]3[N:45]=[C:44]([NH:46][CH2:47][CH3:48])[C:43]4=[N:58][CH:59]=[C:60]([C:61]#[N:62])[N:42]4[N:41]=3)[C:32]=2[Cl:63])[CH2:21]1)=[O:18])([OH:8])([OH:7])=[O:5]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)CCCOP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To a solution of (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-((di-tert-butoxyphosphoryl)oxy)butanoate (72 mg, 0.079 mmol) in DCE (2 mL) at 0° C. was added TFA (25% in DCE) (6.10 mL, 19.79 mmol) followed by anisole (0.035 mL, 0.317 mmol) and stirred at 35° C. for overnight. After completion of the starting material (by LC-MS), reaction was concentrated and purified by reverse phase preparative HPLC and collected fractions were lyophilized to give (3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 4-(phosphonooxy)butanoate (4 mg) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[NH:12][C:13]2[C:18]([C:19]=1[O:20]C(=O)C(C)(C)C)=[CH:17][CH:16]=[CH:15][N:14]=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]([F:38])[F:37]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:11](=[O:27])[N:12]([CH2:35][CH:36]([F:38])[F:37])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[CH:15][N:14]=2
Reactant: CC(C)(C)C(=O)Oc1c(-c2c(F)ccc(F)c2Cl)c(=O)[nH]c2ncccc12
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2c(F)ccc(F)c2Cl)c(O)c2cccnc2n1CC(F)F
Temperature: 120 °C

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-chloro-3,6-difluoro-phenyl)-2-oxo-1,2-dihydro-[1,8]naphthyridin-4-yl ester (Example 1.5) (0.2 g), potassium carbonate (0.211 g) and 1-bromo-2,2-difluoro-ethane (0.15 g) in N,N-dimethylformamide (3 ml) was heated to 120° C. in a microwave for 15 minutes. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic phase was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. D21 of Table D as a colourless oil (24 mg).
Reaction SMILES: [C:1]([C:4]1[C:12]2[NH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:2][C:1]([C:4]1[C:12]2[NH:11][CH:10]=[CH:9][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C(N)=O)c2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(C(=O)O)c2cc[nH]c12
Yield: 135.1 %

Procedure:
4: To a solution of tert-butyl 7-carbamoyl-1H-indole-4-carboxylate (0.15 g, 0.58 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL), and the mixture was heated to reflux until the starting material was fully consumed. The solvent was evaporated followed by rotary evaporation of the residue from a mixture of ethyl acetate (50 mL) and toluene (50 mL). The procedure was repeated three times and the residue dried in vacuo to obtain 7-(aminocarbonyl)-1H-indole-4-carboxylic acid (0.16 g, 89%). MS (EI) for C10H8N2O3: 205 (MH+).
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:32][O:33][C:34](=[O:39])[C@H:35]([CH2:37][OH:38])[NH2:36]>C1COCC1>[CH3:32][O:33][C:34](=[O:39])[CH:35]([NH:36][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1([CH3:3])[O:5][CH2:6][CH2:7][O:8]1)[CH2:37][OH:38]
Reactant: CC1(CCCCC(=O)O)OCCO1
Reactant: COC(=O)[C@@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(CO)NC(=O)CCCCC1(C)OCCO1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(2-methyl-[1,3]dioxolan-2-yl)-pentanoic acid (4.78 g, 25.40 mmol) in THF (165 mL) at −30° C. was treated sequentially with Et3N (7.50 mL, 53.33 mmol) followed by isobutyl chloroformate (3.81 mL, 27.94 mmol). After stirring for 1 h at −30° C., serine methylester hydrochloride (4.43 g, 37.94 mmol) was added and the reaction mixture was allowed to warm gradually to rt over 3 h and stirred for an additional 16 h at rt. The resulting suspension was filtered, the solid washed with THF and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (9:1:0→0:9:1 hept-EA-MeOH) gave the title compound as a colorless oil. TLC: rf (1000:50:4 CH2Cl2-MeOH—NH3)=0.1. LC-MS-conditions 02: tR=0.63 min [M+H]+=290.25.
Reaction SMILES: C[O-].[Na+].N#N.[C:6]([O:9][CH3:10])(=[O:8])[CH3:7].[CH:11]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)=O>O1CCCC1>[NH:17]1[C:18]2[C:14](=[C:13]([CH:11]=[CH:7][C:6]([O:9][CH3:10])=[O:8])[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: COC(C)=O
Reactant: O=Cc1cccc2[nH]ccc12
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
48 g of sodium methoxide are added to 300 ml of tetrahydrofuran with stirring at 5° C. under a protective gas (N2), the suspension is cooled to 0° C., 70 ml of methyl acetate are added dropwise at from 0 to 3° C., and the mixture is stirred at this temperature for a further 45 minutes. A solution of 43 g of 4-formylindole (3) in 300 ml of tetrahydrofuran is subsequently added with stirring, during which the temperature does not exceed 3° C. The mixture is subsequently stirred at room temperature for a further two hours. For work-up, the reaction mixture is evaporated, and the residue is dissolved in methyl acetate and extracted with water. The organic phase obtained is dried, the solvent is removed under reduced pressure, and the residue is purified by chromatography on silica gel, giving 35 g (59% of theory) of a pale-beige crystalline residue of methyl 3-(1H-indol-4-yl)acrylate (4).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([C:8]([OH:10])=O)[CH2:6][N:5]([CH3:11])[C:4]1=[O:12])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][NH2:53]>ClCCl>[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[CH2:52][NH:53][C:8]([CH:7]1[CH2:6][N:5]([CH3:11])[C:4](=[O:12])[N:3]1[CH2:1][CH3:2])=[O:10]
Reactant: CCN1C(=O)N(C)CC1C(=O)O
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCN1C(=O)N(C)CC1C(=O)NCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
A mixture of 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (138 mg, 0.800 mmol), 1-hydroxybenzotriazole hydrate (147 mg, 0.960 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.960 mmol) and N-ethyl morpholine (0.409 ml, 3.20 mmol) in dichloromethane (9 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (141 mg, 0.8 mmol) in dichloromethane (1 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (10 ml) and the solution was washed with saturated sodium hydrogen carbonate solution (10 ml), water (10 ml), citric acid solution (10 ml) and brine (10 ml), dried and evaporated. The residue was purified by mass-directed automated HPLC. The residue was triturated with ether and the resulting solid was collected and dried to give N-[(2,4-dichlorophenyl)methyl]-3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxamide (141 mg, 53%). LC/MS [M+H]+=330, retention time=2.36 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][CH3:21])[CH2:12]1)(=[O:10])=[O:9].[CH2:22]1[C:24]([NH2:27])([C:25]#[N:26])[CH2:23]1.Cl>>[C:25]([C:24]1([NH:27][C:16]([C@@H:14]2[CH2:15][CH:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:12][C@H:13]2[CH2:19][O:20][CH3:21])=[O:18])[CH2:22][CH2:23]1)#[N:26]
Reactant: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)O
Reactant: N#CC1(N)CC1
Agent: Cl
Product: COC[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was synthesized in analogy to Example 68/69, Step 11, from (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-methoxymethyl-cyclopentanecarboxylic acid (epimeric mixture) and 1-amino-cyclopropyl cyanic hydrochloride to afford the desired product as a yellow foam. MS (EI): 397.0 (M+H)+.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.C([O-])(=O)C.[Na+].[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24](Br)[C:23]2=[O:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:23]2=[O:29])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C=C(Br)C(=O)N1c1ccccc1
Reactant: CCCCCCS
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCSC1=CC(=O)N(c2ccccc2)C1=O
Yield: 48.1 %

Procedure:
To hexanethiol (111 μL, 0.79 mmol) and sodium acetate trihydrate (108 mg, 0.79 mmol) in methanol (60 mL) was added in N-phenyl monobromomaleimide (200 mg, 0.79 mmol) in methanol (60 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow solid (109 mg, 0.38 mmol) in 48% yield. δH (600 MHz, CDCl3) 7.45 (dd, 2H, J=7.1 and 8.0, 2×H-12), 7.36 (d, 2H, J=6.0, H-11), 7.35 (d, 2H, J=8.1, 2×H-13), 6.19 (s, 1H, H-2), 2.96 (t, 2H, J=7.9, H2-10), 1.81-1.76 (m, 2H, H2-9), 1.50-1.45 (m, 2H, H2-8), 1.34-1.32 (m, 4H, H2-6 and H2-7), 0.91 (t, 3H, J=6.9, H3-5); δC (125 MHz, CDCl3) 168.59 (C═O), 166.96 (C═O), 152.20 (C3), 131.53 (C14), 129.21 (2×Ar—H), 127.93 (C11), 126.09 (2×Ar—H), 117.24 (C2), 32.03 (C10), 31.33 (CH2), 28.68 (CH2), 27.78 (CH2), 22.59 (CH2), 14.11 (C5); IR (oil, cm−1) 2931 (w), 1703 (s); MS (CI+) m/z (relative intensity): 290 ([M+H], 100); Exact Mass Calcd for [C16H20NO2S]+H requires m/z 290.1215 Found 290.1224 (CI+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]([C:36]([O:38]C)=[O:37])=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=3[CH:35]=2)=[CH:14][CH:15]=1)(=[O:3])[NH2:2].CO.[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]([C:36]([OH:38])=[O:37])=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=3[CH:35]=2)=[CH:14][CH:15]=1)(=[O:3])[NH2:2]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4C(N)=O)c(C(=O)OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3ccc(-c4ccccc4C(N)=O)c(C(=O)O)c3)cc12
Yield: 95.6 %

Procedure:
To a 25 mL round-bottomed flask was added methyl 2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate (58.3 mg, 0.107 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents of a 1M solution of sodium hydroxide (0.856 mL, 0.856 mmol). The mixture was diluted with 20 mL of ethyl acetate, made acidic with 0.5M HCl and the crude product was extracted, washed with brine, and dried over sodium sulfate. The product solution was filtered and evaporated to dryness giving 52 mgs (98% yield) of 2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylic acid as a yellow solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 nm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. LCMS m/z 509.3 (M+H), Rt=2.695 min., 90% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 3-chloro-4-hydroxy-benzoic acid (1.0 g, 5.8 mmol) in methanol (30 mL) was added sulfuric acid (3 mL, 56.3 mmol) and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. The residue was partitioned between a saturated solution of K2CO3 and ethyl acetate (3×30 mL), dried, filtered and concentrated in vacuo to yield methyl 3-chloro-4-hydroxy-benzoate (0.9 g, 83%) as a white solid. ESI-MS m/z calc 186.5. found 187.5 (M+1)+; Retention time: 1.17 minutes (3 min run). 1H NMR (400.0 MHz, CDCl3) δ 8.05 (d, J=2.2 Hz, 1H), 7.90-7.87 (dd, J=8.8, 2.2; H, 1H), 7.06 (d, J=8.8 Hz, 1H) and 3.90 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[N-:17]=[N+:18]=[N-:19].[Na+].Cl[Si](C)(C)C>C1(C)C=CC=CC=1.C(#N)C.O>[CH3:10][N:9]1[C:7]([C:6]2[CH:11]=[CH:12][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)=[N:19][N:18]=[N:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1ccc(CCl)cc1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cn1nnnc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(chloromethyl)-N-methyl-benzamide (50 mmol) in toluene (200 mL) was added thionyl chloride (29.1 mL, 400 mmol) at room temperature. The resulting suspension was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was azeotroped with toluene and dried under high vacuum. To a suspension of sodium azide (4.55 g, 70 mmol) in acetonitrile (100 mL) was added chlorotrimethylsilane (9.15 mL, 73.4 mmol) at room temperature and the suspension was stirred for 1.5 hours. The reaction mixture was cooled to −10° C. and the above crude imidoyl chloride (50 mmol) in acetonitrile (65 mL) was added over 5 minutes. The mixture was stirred for 2 hours at 0° C. and then stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C. The resulting solution was stored in the refrigerator overnight and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, 4-(1-methyltetrazol-5-yl)benzyl chloride was isolated as 6.26 g (60%) of a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.76 (d, J=8.2 Hz, 2 H), 7.61 (d, J=8.2 Hz, 2 H), 4.67 (s, 2 H), 4.20 (s, 3 H). HRMS (ES+) cald. for C9H9ClN4 [(M+H)+] 209.0589, obsd. 209.0588.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1>>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccco1
Product: c1coc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with furfurylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 292.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H); 8.45 (s, 1H); 8.18 (m, 1H); 7.87 (m, 1H); 7.40 (m, 4H); 6.86 (d, J=5.5 Hz, 1H); 6.35 (m, 1H); 5.71 (br s, 1H); 4.75 (d, J=5.0 Hz, 2H).