Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.Cl.[CH3:31][NH:32][CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:31][N:32]([CH3:33])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: CNC
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1nc2ccccc2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@@H]1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CN1
Reaction time: 0.02 h

Procedure:
To a solution of (2S,4S)-4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00969 mmol) in DMF (2 mL) at rt were added dimethylamine hydrochloride (20 mg, 0.25 mmol) and DIPEA (0.1 mL, 0.6 mmol), and the mixture was stirred for 1 min. TBTU (6.22 mg, 0.0194 mmol) was then added, and the solution was stirred for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the product was collected and filtered off with 1:1 MeOH/DCM. The filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.21 (m, 1H), 2.82-2.91 (m, 1H), 3.00 (s, 3H), 3.12 (s, 3H), 3.23 (dd, J=12.4, 6.3 Hz, 1H), 3.49 (dd, J=12.0, 3.4 Hz, 1H), 4.15 (t, J=8.3 Hz, 1H), 4.98-5.05 (m, 1H), 7.42-7.47 (m, 1H), 7.53 (td, J=7.7, 1.3 Hz, 1H), 7.85 (s, 1H), 8.02 (dd, J=11.6, 7.8 Hz, 2H), 8.13 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H). MS (ES+): m/z=434.14 (100) [MH+]. HPLC: tR=2.12 min (ZQ2, polar—5 min).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.[NH:30]1[CH:34]=[C:33]([C:35](O)=O)[N:32]=[CH:31]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:35]([C:33]5[N:32]=[CH:31][NH:30][CH:34]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Reactant: O=C(O)c1c[nH]cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: c1ccc(-c2cc3c(ccn4c(-c5c[nH]cn5)nnc34)nc2-c2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-4 (0.2 g, 0.5 mmol), 1H-imidazole-4-carboxylic acid (0.06 g, 0.5 mmol), HOBT (0.06 g, 0.5 mmol), and DIEA (0.2 ml, 1.4 mmol) in DMF (2 ml) was added EDC (0.1 g, 0.6 mmol). The solution was stirred at room temperature for 45 min and was then heated at 80° C. in the microwave for 15 min. The solvent was removed in vacuo. The residue was taken up in DMF (0.5 ml) and was treated with glacial AcOH (2.0 ml). The reaction mixture was heated at 80° C. for 45 min. The reaction was then quenched with water (10 ml) and extracted into EtOAc (3×20 ml). The combined organic layers were concentrated in vacuo to give 22-1 as a brown residue.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:9]=2[CH:23]=1)(O)=[O:3].[NH3:24]>CN(C)C=O.C(Cl)Cl.O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([CH3:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:9]=2[CH:23]=1)(=[O:3])[NH2:24]
Reactant: N
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(N)=O)cc2n1Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxylyl chloride (0.437 g) is added to a methylene chloride (8 ml) solution of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.490 g) and N,N-dimethylformamide (1 drop) under ice-chilled conditions, and the solution is stirred for 1.5 hours at room temperature. Then, 28% aqueous ammonia (4 ml) is added and the solution is stirred for 12 hours at room temperature. Water and methylene chloride are added to the reaction solution for extraction. After the organic layer is concentrated, precipitated crystals are collected, dried and 6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.240 g) is obtained. 1H-NMR (DMSO-d6, δ): 2.48 (3H, s), 5.54 (2H, s), 6.41 (1H, d, J=8.4 Hz), 7.21-8.02 (3H, m), 7.31 (1H, dd, J=2.2 and 8.4 Hz), 7.60 (1H, d, J=8.4 Hz), 7.75 (1H, m), 7.93 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=O)[CH2:6]Br)[CH3:2].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O1CCOCC1>CC#N>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:9])[N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: CCOC(=O)c1cn2c(cnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 72 h
Yield: 75.5 %

Procedure:
3-Bromo-2-oxo-propionic acid ethyl ester (0.090 mL, 0.72 mmol) was added to a mixture of 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (0.180 g, 0.624 mmol, prepared using E from Example #3 Step E and HCl) and 1,4-dioxane (3.5 mL) under nitrogen. After about 3 days, the volatiles were removed under reduced pressure. The residue was slurried in Et2O (5 mL) and then filtered to afford a tan powder. The solid was slurried in MeCN (3.50 mL) under nitrogen. PFPAA (0.40 mL, 2.1 mmol) was added. After about 30 min, the volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO3/water (2:1, 20 mL). The aqueous layer was extracted with DCM (20 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to afford ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-7-carboxylate (0.181 g, 75%): LC/MS (Table 1, Method n) Rt=0.70 min; MS m/z: 385 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.O[C:10]1C=CC(C2C=C[C:19]([OH:22])=CC=2)=CC=1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>>[CH3:10][O:7][C:6]1[CH:5]=[CH:4][C:3]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:2][CH:1]=1.[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:1][C:2]=1[C:19]([OH:22])=[O:30]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Product: O=C(O)c1ccccc1Br
Yield: 35 %

Procedure:
However, Busch et al. found that with aromatic compounds containing polar substituents, the selectivity to biphenyls was much lower. For example, p-bromophenol gave ca. 13.4% 4,4'-dihydroxybiphenyl, p-bromoanisole gave ca. 35% 4,4'-dimethoxybiphenyl, bromobenzoic acid gave 40% 4,4'-biphenyldicarboxylic acid and 3-bromobenzoic acid gave 56.5% 3,3'-biphenyldicarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].CO/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.Cl>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(OC)c1OC
Reactant: CO/C=C/C(=O)OC
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc(OC)c(OC)c1OC
Reaction time: 16 h
Yield: 25 %

Procedure:
1.68 g of 1,2,3-trimethoxybenzene, 1.34 g of methyl trans-3-methoxyacrylate and 6 mL of glacial acetic acid were mixed, 313 mg of 35 wt % hydrochloric acid was added into the mixture at an inner temperature of 25° C., the added mixture was stirred for 16 hours at the same temperature to cause a reaction. After completion of the reaction, 30 mL of water and 50 mL of ethyl acetate were added into the reaction liquid, and extraction treatment was conducted. The resultant organic layer was washed with water, then, concentrated, and the resultant concentrated residue was purified by silica gel column chromatography (developing liquid: n-heptane/ethyl acetate=6/1 to 5/1), to obtain 0.63 g of methyl trans-3-(2,3,4-trimethoxyphenyl)acrylate (white solid). 0.92 g of the raw material 1,2,3-trimethoxybenzene was recovered. The yield of methyl 3-(2,3,4-trimethoxyphenyl)acrylate based on the converted 1,2,3-trimethoxybenzene was 55%.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:33])([F:1])[CH2:3][CH2:4]2)=[O:9])=[CH:37][CH:36]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To the solution of 0.15 (0.37 mmol) (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20) in 5 ml dichloromethane. 0.13 g (0.74 mmol) copper(II) acetate, 0.17 g (1.1 mmol) 4-chlorophenylboronic acid and 0.12 ml (0.12 mg, 1.5 mmol) pyridine were added and the suspension was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give the compound as a light yellow solid (88%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40]Br>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@@H:24]5[CH2:28][C@@H:27]([F:29])[CH2:26][N:25]5[CH2:40][CH2:39][O:38][CH3:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1C[C@@H](F)CN1
Reactant: COCCBr
Product: COCCN1C[C@H](F)C[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoro-1-(2-methoxyethyl)pyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S,4R)-4-fluoropyrrolidin-2-yl]methyl}-1,3-thiazolidine-2,4-dione (Example 184) and 2-bromoethyl methyl ether following General Procedure S.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:16]([OH:17])[OH:15])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1cnc2ccccc2c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromoquinoline (Sigma-Aldrich, St. Louis, USA) (1 eq, 14.0 mmol, 1.94 ml) in toluene/THF (4:1, 25 ml), triisopropylborate (1.2 eq, 16.8 mmol, 3.94 ml) is added. The mixture is cooled to −40° C., then n-butyl lithium (1.6 M in THF, 1.2 eq, 17 mmol, 10.5 ml) is added within 30 min. After stirring for additional 30 min at this temperature, the cooling bath is removed and the reaction mixture is allowed to to warm up to −20° C. before quenching with aqueous HCl solution (2 N). The mixture is adjusted to pH 7 by using aqueous NaOH solution (4 N), then it is saturated with NaCl, and extracted with THF. The organic layer is concentrated in vacuo, and the resulting solid is recrystallized in MeCN yielding the title compound, [M+H]+=173.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O>C(OC(=O)C)(=O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C(=O)CNC(=O)c2ccncc2)cc1
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-c2cnc(-c3ccncc3)o2)cc1
Temperature: 40 °C
Yield: 72 %

Procedure:
α-isonicotinamido-p-methoxyacetophenone (11.5 g., 0.043 mole) was added portion-wise to a stirred solution of 200 ml of acetic anhydride and 15 ml of 90% phosphoric acid; during the addition an exotherm raised the reaction temperature to 40° C. After the addition was complete the reaction mixture was stirred and refluxed for 2 hours. After cooling, the supernatant liquid was decanted from the viscous precipitate, which was crystallized by titration with 350 ml of 1% aqueous sodium hydroxide. The yellow solid was filtered, washed with distilled water (200 ml), and dried in vacuo yielding 7.76 g. (yield 72%) of 2-(4-pyridyl)-5-p-methoxyphenyloxazole, m.p. 105°-107° C.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH2:12])=O)=[CH:6][C:5]=12.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:12])=[CH:6][C:5]=12
Reactant: NC(=O)c1ccn2ccnc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccn2ccnc2c1
Yield: 93.1 %

Procedure:
To a solution of Imidazo[1,2-a]pyridine-7-carboxylic acid amide (38 mg, 0.24 mmol) and triethylamine (0.066 ml, 0.47 mmol) in CH2Cl2 (5 ml) was added trifluoroacetic anhydride (0.39, 2.83 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 h before the crude mixture was loaded onto a SCX SPE cartridge, washing with MeOH and eluting with the product with 2M NH3/MeOH. Removal of solvent in vacuo afforded the title compounds (32 mg). MS: [M+H]+143.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C>O1CCCC1>[CH3:1][S:2]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][Br:6])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CBr)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Methanesulfonyl chloride (50 g, 436 mmol) was added to a solution of 2-bromo-1-(4-hydroxyphenyl)-ethan-1-one (85 g, 395 mmol) and triethylamine (48 g, 474 mmol in tetrahydrofuran (1000 ml) at 0° C. and the mixture was stirred for 30 minutes at room temperature. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with brine, dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diisopropyl ether to afford 4-(2-bromoacetyl)phenyl methanesulfonate (96 g, 83%) as white crystals.
Reaction SMILES: [CH2:1]1[C:6](=O)[N:5]([Br:8])[C:3](=[O:4])C1.CNC(=O)[O-:12].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1>CC#N.O.CCOC(C)=O>[CH2:6]([NH:5][C:3](=[O:12])[O-:4])[CH3:1].[CH3:14][O:15][C:16]1[C:17]([Br:8])=[CH:18][C:19]2[CH:20]([CH3:28])[CH:21]3[CH2:25][NH:24][CH2:23][CH:22]3[C:26]=2[CH:27]=1
Reactant: CNC(=O)[O-]
Reactant: COc1ccc2c(c1)C1CNCC1C2C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCNC(=O)[O-]
Product: COc1cc2c(cc1Br)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
NBS (70 mg, 0.4 mmol) was added to a solution of N-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.1 g, 0.36 mmol) in CH3CN (3.6 mL), and stirred overnight at room temperature. The reaction was diluted with H2O and EtOAc and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated to afford 120 mg (94%) of the subtitle compound. MS calculated for C16H20BrNO3+H: 342, observed: 342.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4].[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(O)(=O)C.[Na]>ClCCCl>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][CH2:2][CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: NCC(O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: [Na]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCC(O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
2-Amino-1-pyridin-2-yl-ethanol (0.700 g, 5.07 mmol) and N-boc-piperidone (1.20 g, 5.90 mmol) was dissolved in 5 mL of 1,2-dichloroethane. Glacial acetic acid (0.40 mL, 7.0 mmol) was added followed by sodium tricaetoxyborohydride (2.00 g, 8.97 mmol). This mixture was stirred at room temperature under argon for 16 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel 12 g, eluted with dichloromethane, MeOH and ammonium hydroxide 100 to 95:4.9:0.1) to give 4-(2-hydroxy-2-pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil (1.46 g, 90%).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:25]([CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH3:27])[CH2:24][NH:23][CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:25]([CH:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)[CH3:27])[CH2:24][N:23]([C:7]([Cl:10])=[O:6])[CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 126.8 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (29 mg, 0.098 mmol) in CH2Cl2 (2 mL) at −78° C., was added a solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (intermediate XV-B-1) (100 mg, 0.25 mmol) and pyridine (0.043 mL, 0.54 mmol) in CH2Cl2 (2 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded 58 mg (50%) of the title compound as a light yellow solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
As described in Example 44, 8.14 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with p-trifluoromethylphenol to give 7.7 g of off-white crystals. Recrystallization from methanol gives the product as white crystals, mp 83°-84° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[NH:33]1[CH:37]=[N:36][CH:35]=[N:34]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(c1ccc(-n2cncn2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Yield: 26.2 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.7 g), 60% sodium hydride in oil (0.5 g, degreased with hexane), 1,2,4-triazole (0.70 g) and dimethylformamide (50 ml), the title compound (0.51 g) was obtained as an amorphous solid, MS, m/z: 390.3 (M+H)+, 779.3 (2M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NCCCCNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Carbomethoxybenzoyl chloride (19.07 g, 0.096 mol) was dissolved in toluene (380 mL) in a 3-necked, 1000 mL round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel A solution of 1,4-butanediamine in water (80 mL) was added dropwise over a period of 40 minutes while the temperature of the reaction mixture was maintained at 25° C. by a water bath. A white solid formed immediately and the reaction mixture stirred for an additional 2 hours. The solid was collected on a frit and washed with toluene, water, 5% HCl, and water. Recrystallization from DMF gave white crystals which were dried in a vacuum oven at 60° C.; yield 17.91 g (90%); m.p. 260°-261° C. 1H NMR (200 MHz, DMSO-d6) δ8.70 (2H, m), 8.05-7.93 (8H, m) 3.88 (6H, s) 3.34 (4H, s), 1.58 (4H, s); IR (nujol) 3300, 1720, 1625, 1530, 1275, 1105, 860, 730 cm-1 ; low res. MS (CI, isobutane) 413 (MH+); 13C NMR (75 MHZ, DMSO-d6) δ166.9, 165.7, 165.4, 165.2, 138.7, 131.6, 129.0, 127.5, 127.2, 52.3, 26.5.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C1C[C@@H](C(O)=O)NCC1.C(=O)([O-])[O-].[Na+].[Na+].BrCC(C1C=CC=CC=1)=O>CO>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 152.5 %

Procedure:
Using the procedure described in example 5, 55 mg (0.17 mmol) of L-homoproline-L-isoleucine benzylamide (prepared from L-homoproline (Bachem Bioscience, Philadelphia, Pa.) using the procedure described in examples 3, and 4), was treated with sodium carbonate (39 mg, 0.37 mmol), and 2-bromoacetophenone (59 mg, 0.29 mmol, 1.7 eq) in methanol (5 mL). A sample of the crude mixture was purified by preparative TLC to provide 34 mg (45%) of L-isoleucine, N-[1-(2-phenyl-2-oxoethyl)-L-homoproline] benzylamide.