Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29]>>[C:24]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]1[CH2:14][CH2:15][CH:3]([NH:2][C:28](=[O:29])[N:27]([CH3:31])[CH3:26])[CH2:4][C:5]2=1)#[N:25]
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CN(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Yield: 69 %

Procedure:
Prepare the title compound by essentially following the procedures as described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile hydrochloride (Preparation 54) and dimethylcarbamyl chloride. Purify by silica gel chromatography (30-70% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 69% yield as a white solid. MS (ES): m/z 391 (M+1), 389 (M−1); HPLC (Method B): Rt=4.11 min (99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCOCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and N-(2-bromophenyl)morpholine-4-sulfonamide. MS (ESI): mass calcd. for C20H20FN5O3S, 429.13; m/z found, 430.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 8.34 (d, J=1.4, 1H), 8.14 (m, 1H), 7.63 (d, J=8.0, 1H), 7.43-7.35 (m, 1H), 7.31 (dd, J=8.0, 1.7, 1H), 7.24-7.19 (m, 2H), 6.39 (s, 1H), 3.67 (dd, J=5.8, 3.7, 4H), 3.23-3.14 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15]C3C=CC=CC=3)[C:8]=2[C:22]#[N:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C>[C:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([SH:15])[C:8]=2[C:22]#[N:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cnc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: N#Cc1cnc(S)c(C#N)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
918 mg (2.928 mmol) of 4-phenyl-2-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 36A) were initially charged in 10.7 ml of DMF. 274 mg (3.514 mmol) of sodium sulfide were added, and the reaction solution was then stirred at 80° C. for 3 h, and after 1.5 h another 274 mg (3.514 mmol) of sodium sulfide were added. The mixture was stirred at RT overnight. 5.85 ml of 1N hydrochloric acid were added to the reaction mixture, and the reaction solution was evaporated. 5 ml of tetrahydrofuran were added to the residue, and the precipitate formed was filtered off and discarded. The filtrate was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1COC1C=CC(C(O)=O)=CC=1.C[O:23][C:24](=[O:44])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[C:27]([Cl:43])[CH:26]=1>>[Cl:43][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)[C:24]([OH:44])=[O:23]
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
Following the procedure for the preparation of 4-(Quinolin-2-ylmethoxy)-benzoic acid but substituting 3-Chloro-4-(quinolin-2-ylmethoxy)-benzoic acid methyl ester provided the title compound. (M+H m/z=314.0).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][C@@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@H:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:15][C@@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Reactant: CC(C)(C)[C@H](N)CO
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aS,5aS)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=8.0, 4.7 Hz, 1H), 2.26-2.32 (m, 1H), 2.74-2.78 (m, 1H), 2.94 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7, 6.1 Hz, 1H), 3.67-3.72 (m, 1H), 3.93-3.98 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 8.42 (dd, J=1.4, 0.9 Hz, 1H), 8.51 (d, J=2.7 Hz, 1H), 9.26 (d, J=1.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[C:17]([CH2:18]Br)=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1)=[O:10].C[Si](C)(C)N[Si](C)(C)C.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11][C:9]1=[O:10]
Reactant: CSc1ncc(CBr)c(NC(=O)Nc2ccccc2Cl)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Temperature: 110 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a suspension of [(2-chlorophenyl)amino]-N-[5-(bromomethyl)-2-methylthiopyrimidin-4-yl]carboxamide (1360 g, 3.62 mole) of in 10 L 1-methyl-2-pyrrolidinone was added 136 mL hexamethyldisilazane. The mixture was heated to an internal temperature of 105-115° C. for 1.5 hours. The mixture was then cooled to 30° C. and treated with 20L water. The mixture was then stirred at 5-8° C. for 2 hours and filtered. The filters were collected and washed sequentially with water and hexanes. The product was placed in a drying oven and heated under vacuum for 16 hours to give 780 g (70.1%) of 3-(2-chlorophenyl)-7-methylthio-3,4-dihydropyrimido[4,5-d] pyrimidin-2(1H)-one (sulfide 10.1) as an off-white solid. (M+1 308)
Reaction SMILES: [H-].[Na+].S([NH:13][N:14]=[C:15]([CH2:17]P(OCC)(OCC)=O)[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([C:32]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CCOP(=O)(CC(C)=NNS(=O)(=O)c1ccc(C)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(-c3ccccc3)cc2)[nH]n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred mixture of NaH (1.98 g, 0.049 mol, 60% oil dispersion) in dry THF (30 mL) was added a suspension of diethoxyphosphorylacetone tosyl hydrazone (8.97 g, 0.024 mol; N Almirante Syn. Lett. 1999, 302.) in a mixture of THF (35 mL) and DMF (5.0 mL) dropwise over 15 min. The yellow suspension was stirred at 0-5° C. for 30 min and was treated with a 4-biphenyl carboxaldehyde (3.10 g, 0.0169 mol) in dry THF (30 mL) at 0-5° C. over 15 min. The orange solution was heated and stirred at reflux for 4 h and stirred at ambient temperature overnight. The mixture was poured into 5% aq. NaH2PO4 (350 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated to a yellow semi-solid. This material was triturated with hot EtOAc (20 mL) and filtered. The solid was washed with EtOAc (2×10 mL) and dried under high vacuum to give the title compound (2.61 g, 47%): HRMS Calculated for C16H15N2: m/z 235.1235. Found: 235.1230.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH:20]([NH:22][NH2:23])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:20]=[N:22][N:23]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: NNC=O
Solvent: CCCCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2

Procedure:
A mixture of 5.74 g. (0.020 mole) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 3.6 g. (0.060 mole) of formic acid hydrazide and 200 ml. of 1-butanol was refluxed for 3.75 hours with a slow stream of nitrogen bubbling through the mixture. The mixture was concentrated, the residue was suspended in water, and the suspension was filtered. The filter cake consisted principally of unchanged starting material. The filtrate was concentrated, ethyl acetate and Skellysolve B hexanes being added during the concentration, giving crude product (2.54 g.) of melting point 220.5°-225° C. Recrystallization of this material from ethyl acetate-Skellysolve B hexanes gave 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 228°-229° C. The ultraviolet spectrum (ethanol) had end absorption λ max. 222 (ε = 40,950) and inflections at 245 (ε = 16,200) and 285 mμ(ε = 3,500).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:24][CH:21]3[CH2:23][CH2:22]3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NC1CC1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NC1CC1
Yield: 85.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and cyclopropylamine (50 μL, 0.5 mmol) to give 143 mg of the title compound (86%): mp 265°~268° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 bs, 1H), 8.04 (d, 1H, J=4 Hz), 7.20 (d, 1H, J=2 Hz), 7.14 (d, 1H, J=2 Hz), 5.05~5.14 (m, 1H), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.77 (dm, 1H, J=17.1 Hz), 2.54~2.64 (m, 2H), 2.35 (dd, 1H, J=16.2, 4.5 Hz), 2.25 (dd, 1H, J=16.2, 11.7 Hz), 2.00 (dm, 1H, J=13.5 Hz), 1.73~1.87 (m, 1H), 0.56~0.64 (m, 2H), 0.32~0.41 (m, 2H).
Reaction SMILES: C(O)CO.[CH2:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9].[C:11](O)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](O)=[O:17]>CN(C)C=O>[CH2:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9].[CH2:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: O=C(O)CCCCC(=O)O
Solvent: OCCO
Solvent: OCCCCO
Solvent: CN(C)C=O
Product: OCCCCCCO

Procedure:
Top coat solution D1 is a 25% solution of a polyester urethane in dimethylformamide (DMF)/methyl ethyl ketone (MEK) (1:1) with a viscosity of 10,000 cP/25° C. The polyester urethane elastomer is obtained from 2000 g (1.0 mol) of a copolyester of ethylene glycol/butane-1,4-diol and adipic acid (molecular weight 2000), 108.0 g (1.20 mol) of butane-1,4-diol, 141.6 g (1.20 mol) of hexane-1,6-diol and the equivalent quantity of 4,4'-diphenylmethane diisocyanate (850 g) by a one-shot process. The molar ratio of chain-lengthening agents is therefore 1:1.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16](Br)=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26]>>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C:21]4=[O:26])=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1c1cnc(OC2CCN(C3CCCC3)CC2)nc1

Procedure:
According to the same method as in Example 17 but using 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine and piperidin-2-one, the entitled compound was obtained.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[F:21][CH:22]1[CH2:26][NH:25][C@H:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:25]1[CH2:26][CH:22]([F:21])[CH2:23][C@H:24]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(F)CN1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(N2CC(F)C[C@H]2C(=O)OC(C)(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.06 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 685 mg of the compound obtained in Step 12-2 as starting materials, respectively 678 mg (Isomer A: colorless solid) and 839 mg (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O>>[O:31]=[C:22]1[N:21]([C:17]2[CH:16]=[C:15]([F:32])[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:19]([F:20])[CH:18]=2)[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2,6-difluorophenyl]-1-piperdinecarboxylic 1,1-dimethylethyl ester ((EXAMPLE 35, Step 7, 847 mg) and trifluoroacetic acid (12 mL) maintained at 0° C. under N2 is stirred for two hours and then concentrated under reduced pressure to remove excess trifluoroacetic acid. The residue is diluted with saturated aqueous potassium carbonate (70 mL) and methylene chloride (50 mL), and the layers are separated. The aqueous phase is extracted with methylene chloride (2×50 mL), and the combined organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure, triturated with diethyl ether and recrystallized from ethyl acetate to give the title compound, NMR (CDCl3, 400 MHz) 7.08, 6.10, 4.78, 4.00, 3.74, 3.64, 3.19, 3.07, 2.72, 2.03, 1.99, 1.68 δ.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([OH:52])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:65][CH2:66]I)(=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61].O>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH2:66][O:65][C:59](=[O:64])[C:60]([CH3:63])([CH3:62])[CH3:61])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nc2cccc(C(=O)OCOC(=O)C(C)(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
To a solution of 2-ethoxy-l-[[2'-(N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (2.2 g) in DMF (10 ml) were added potassium carbonate (0.53 g) and pivaloyloxymethyl iodide (0.94 g), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was dissolved in methanol (30 ml) and 1N-HC1 (6 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was concentrated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and dried. After removal of the solvent, the residue was purified by column chromatography on silica gel to give crystals. The crystals were recrystallized from ethyl acetate - hexane to give colorless crystals (1.13 g, 63%), m.p. 104°-106° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH:30]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: CCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To a cold (0° C.) stirred solution of 4-bromo-4′-heptyloxybiphenyl (6.21 g, 17.9 mmol) in THF (120 ml) was added n-BuLi (1.66 M solution in hexane, 32.3 ml, 53.6 mmol). After the mixture was stirred at 0° C. for 20 min., DMF (4.85 ml, 62.6 mmol) was added at −78° C. The mixture was stirred at −78° C. for additional 20 min., and then quenched with sat. aqueous NH4Cl. The mixture was diluted with EtOAc (220 ml), and then successively washed with sat. aqueous NH4Cl. (125 ml) and sat. brine (100 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 1:20) to give 4-formyl-4′-heptyloxybiphenyl (2.21 g, 42%) as a white amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][N+:10]([O-])=O.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[CH2:9][NH2:10]
Reactant: [H][H]
Reactant: O=[N+]([O-])CC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Agent: [Ni]
Solvent: CO
Product: NCC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Yield: 83.8 %

Procedure:
A mixture of 4-(3-(1-(2-fluorophenyl)-2-nitroethyl)-1H-indol-6-yl)morpholine (0.235 g, 0.636 mmol) and Raney Ni (a small spatula) in MeOH (30 mL) was treated with hydrogen at 55 psi in a Parr shaker apparatus for 3 hr. The catalyst was removed by suction filtration. The filtrate was concentrated under vacuum, diluted with CH2Cl2 (100 mL), washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.181 g, 0.533 mmol, 84% yield) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][Cl:21])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: O=C(Cl)CCCl
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CCCl)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and 3-chloropropionyl chloride.
Reaction SMILES: C(N(CC)CC)C.[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>ClCCl>[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(I)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.4 ml) was added to a solution of 4-iodobenzoyl chloride (5.06 g) in dichloromethane (30 ml) at 5° C. Glycine methyl ester hydrochloride (2.4 g) was then added to the reaction mixture and the mixture was stirred at 5° C. for 2 hours. The mixture was then stirred at ambient temperature overnight. Dichloromethane (100 ml) was added and the mixture was washed with water (2×100 ml), dried (MgSO4) and evaported. The residue was triturated with pentane to give a solid which was collected by filtration to give methyl 4-iodohippurate, m.p. 166-168° C. NMR: 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and 9.0(1H,m); m/z 320(M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.Cl.[OH2:22]>>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:22])=[O:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: O
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Product: CCCCCC(C(=O)O)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50 %

Procedure:
A solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.2 g, 0.72 mmol, from Example 5.1, Step 6) in 1.5 mL of CCL4 and 2.2 mL of water containing 4 mg RuCl3 was treated with 628 mg, 2.94 mmol of NaIO4. The mixture was stirred at room temperature for 2.5 h, diluted with 10 mL of water and the pH adjusted to 2 with 10% aqueous HCl. The mixture was extracted with dichloromethane, concentrated to dryness, and purified via flash chromatography (0-20% ethyl acetate/hexane gradient elution) to give 105 mg (50%) of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[S:11])[CH3:2].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]1=[S:11])[CH3:2]
Reactant: CCOC(=O)CNC
Reactant: CCc1ccccc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccccc1N1C(=O)CN(C)C1=S
Yield: 87.4 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 16.3 g of 2-ethylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 20.2 g of triethyl amine, and 300 mL of chloroform. The title compound (20.4 g) was obtained as an off-white solid, m.p. 135°-137° C. Anal. Calcd. for C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found: C, 61.11; H, 5.92; N, 11.71. Mass spectrum (EI, M.+) m/z 234.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Br:9][CH2:10][C:11](Br)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:9][CH2:10][C:11]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:12]
Reactant: O=C(Br)CBr
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 93 %

Procedure:
1,3-Difluorobenzene (100.0 g, 877 mmol) was added to a solution of bromoacetyl bromide (177.0 g, 870 mmol) and aluminum chloride (118.6 g, 890 mmol) in DCM (50 mL) at about 10-15° C. The reaction was then mixed at about 32° C. for about 2 h and then cooled and then added to 3N HCl (650 mL) at about 5-11° C. The solution was warmed to ambient temperature and the product was extracted with pentane (400 mL). The pentane was washed with pH 7 NaCl buffer, concentrated and filtered to afford the title compound (190.1 g, 91%). 1H NMR (DMSO-d6) δ 8.01 (m, 1 H), 7.46 (m, 1 H), 7.27 (m, 1 H), 4.82 (s, 2 H).