Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25].O>CC(N(C)C)=O>[S:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:13]2)[C:3]=1[C:4]#[N:5])(=[O:27])(=[O:26])[NH2:25]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of (S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile (example 5b, 54.55 g, 172.95 mmol) in DMA (110 mL) cooled to 0° C. in an ice bath was added sulfamoyl chloride (55 g, 476 mmol) in two portions (20 g and 35 g). The reaction mixture was stirred for 30 minutes at 0° C. under N2, then at room temperature for 4 hours. The reaction mixture was poured slowly into rapidly stirred cold water (2 L) to provide a milky solution. An additional 800 mL of water was added in several portions to precipitate the desired product (at this point the milky solution has become clear). The precipitate was collected by decantation of the water and was suspended in ethyl acetate (500 mL) then rapidly stirred until it became a fine white solid. The solid material was collected by vacuum filtration and dried under vacuum to give (S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile as a white solid (59.25 g, 150.2 mmol) in 87% yield. MS 395 (MH+)
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethylamide (261 mg) and cesium carbonate (327 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-mercaptophenol (139 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone. The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on a silica gel (using 3:1 dichloromethane:acetone as the eluent) provided the title compound as a beige solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]1([S:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:36]=[CH:35][O:34][C:33]=3[C:37]([OH:39])=[O:38])=[C:28](O)[C:27]=2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]1([S:22]([CH2:25][C:26]2[C:27]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])=[C:28]3[C:29]([C:32]4[CH:36]=[CH:35][O:34][C:33]=4[C:37](=[O:39])[O:38]3)=[CH:30][CH:31]=2)(=[O:23])=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(=O)O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1oc(=O)c1occc12
Reaction time: 72 h
Yield: 137.5 %

Procedure:
N,N′-dicyclohexylcarbodiimide (0.014 g) was added to a solution of 3-[4-(benzenesulfonylmethyl)-3-tert-butoxycarbonyl-2-hydroxyphenyl]-furan-2-carboxylic acid (Intermediate 21, 0.028 g) and DMAP (0.0003 g) in DCM (5 mL) and the mixture was stirred for 72 hours. Water and DCM were added and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 30-40% to give tert-butyl 7-(benzenesulfonylmethyl)-4-oxo-4H-furo[2,3-c]chromene-6-carboxylate (0.037 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:17])[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10](=[O:17])[C:11]3[CH2:12][N:13]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:14][CH2:15][C:16]=3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19]
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CNCC3
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(CCN1CCCCC1)CC3

Procedure:
In the same way as described in Example 5, 5.7 mmoles of 1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pryidin-5-one was alkylated with N-(2-chloroethyl)-piperidine to give, after recrystallization from MeOH, 0.5 g of product; mp 236°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23].[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[C:26]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:22]([O-:24])=[O:23])[CH:11]=2)=[O:15])[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(pyrrolidin-3-yl)thiophene-2-carboxamide (0.15 g, 0.36 mmol) and acetyl chloride (41.0 mg, 0.54 mmol) in tetrahydrofuran (5.0 mL), was added triethylamine (54.2 mg, 0.54 mmol). The resulting reaction mixture was stirred at ambient temperature for 4 hours. After this time, the reaction mixture was quenched with ice water and stirred at room temperature for 20 minutes and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight to afford the title product as an solid (80 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.91 (1H, d), 8.51(1H, m), 3.68 (1H, m), 3.50 (2H, m), 3.23 (2H, m), 2.09 (1H, m), 1.94 (3H, m). MS m/z: 461.17, 363.17 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:9])[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:29]=[O:30].[Cl-].[NH4+]>O1CCCC1>[C:10]1([C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:29]=[O:30])=[CH2:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(c1ccccc1)c1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1cccc(C=O)c1
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A solution of 1-bromo-3-(1-phenylvinyl)benzene (1.00 g, 3.86 mmol) in tetrahydrofuran (5 mL) was stirred under a nitrogen atmosphere at −78° C., and 1.6 M n-butyllithium/hexane solution (3 mL, 4.8 mmol) was added dropwise. After 1 hr, N,N-dimethylformamide (0.372 mL, 4.80 mmol) was added, and the mixture was further stirred at the same temperature for 2 hrs. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (0.626 g, yield 78%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11](=[O:13])[NH2:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:14]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])[CH3:15]>>[C:4]([C:3]1[C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[O:16][CH2:14][CH3:15])=[C:10]([CH:9]=[CH:8][CH:7]=1)[C:11]([NH2:12])=[O:13])(=[O:5])[NH2:6]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: NC(=O)c1cccc(C(N)=O)c1N
Product: CCOc1ccccc1C(=O)Nc1c(C(N)=O)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-carbamoylbenzamide and 2-ethoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as colorless crystals (33%), m.p. 224°-225° C. Found: C,62.57; H,5.18; N,12.81. C17H17N3O4 requires C,62.37; H,5.24; N,12.84%.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:13]1[CH2:14][CH:15]2[CH2:16][N:9]([C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:8])[CH2:10][CH:11]2[CH2:12]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nc4ccccc4o3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-benzooxazole. MS (ESI): mass calculated for C26H23N3O2, 409.49; m/z found 410.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34]([CH:38]([CH3:40])[CH3:39])C(C)C)C.C1(N)CC1>CN(C=O)C>[CH:38]1([NH:34][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH2:12][C:9]4[CH:10]=[N:11][C:5]5[N:4]6[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]6[C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)[CH2:18][CH2:17]3)=[N:20][CH:21]=2)[CH2:40][CH2:39]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: NC1CC1
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and cyclopropanamine (11.15 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 41.2 mg (50%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.81 (s, 1H), 9.85 (br. s., 1H), 8.61 (d, J=2.3 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 8.01 (dd, J=9.0, 2.4 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.42-4.64 (m, 3H), 4.24 (br. s., 2H), 3.92-4.01 (m, 1H), 3.42 (br. s., 2H), 2.94-3.26 (m, 4H), 2.75-2.86 (m, 1H), 2.58-2.73 (m, 1H), 2.03-2.12 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.6 Hz, 1H), 1.31-1.61 (m, 3H), 0.62-0.73 (m, 2H), 0.46-0.57 (m, 2H). [M+H] calc'd for C25H31N7O2, 462; found, 462.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].O>C(Cl)Cl>[Br:30][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(CCCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of {3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL) was added slowly a solution of boron tribromide in methylene chloride (3.8 mL, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. After methylene chloride layer was separated, water and EtOAc were added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (252 mg, 75%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0. 1H NMR (400 MHz, CD3OD): δ 7.92 (s, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 7.38 (m, 2H), 7.03 (t, J=7.2 Hz, 1H), 6.61 (m, 2H), 6.58 (s, 1H), 4.56 (s, 2H), 3.60 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.96 (m, 2H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[N:21][N:20]([CH2:23][CH2:24][CH3:25])[C:18]=2[N:19]=1)[CH3:6].[Br:27][CH2:28][C:29](Br)=[O:30]>ClCCl>[Br:27][CH2:28][C:29]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:26])[C:17]3[CH:22]=[N:21][N:20]([CH2:23][CH2:24][CH3:25])[C:18]=3[N:19]=2)[CH:10]=1)=[O:30]
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
Aluminum trichloride (1.34 g, 0.010 mol) was added portionwise to a stirred solution of 6-(2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 13; 1.0 g, 0.0034 mol) and bromoacetyl bromide (1.35, 0.0067 mol) in dichloromethane (30 ml) at 0° C. The reaction solution was allowed to warm to room temperature, stirred for 14 hours, then for a further 2 hours under reflux. The cool reaction mixture was added dropwise to ice/water (50 g) and the resulting mixture stirred for 1 hour. The organic phase was separated and the aqueous phase extracted with dichloromethane (2×50 ml); the combined organic solutions were then washed with brine (10 ml) and dried (Na2SO4). Removal of the solvent by evaporation under vacuum gave an off-white solid which, when triturated with ether (20 ml) and dried, afforded the product as a white solid (1.29 g, 92%). A sample crystallised from ethyl acetate-hexane as colourless crystals, m.p. 164-166° C. Found: C, 51.88; H, 4.56; N, 13.13. C18H19BrN4O3 requires C, 51.56; H, 4.57; N, 13.36%.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:25][C:18]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([F:15])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 8 h

Procedure:
K2CO3 (8.97 g) and benzylbromide (4.25 mL) were added to a solution of 3-fluoro-4-nitrophenol (5.10 g) in anhydrous DMF (30 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over magnesium sulfate and concentrated. The residual solid was crystallized from EtOAc/hexane to yield 7.31 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-])=O)=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:16])[C:6]2=[O:15].Cl.O>CCO.[Fe]>[NH2:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([Br:1])=[C:3]2[C:7]=1[C:6](=[O:15])[N:5]([CH3:16])[CH2:4]2
Reactant: CN1Cc2c(Br)c(F)cc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1Cc2c(Br)c(F)cc(N)c2C1=O
Yield: 49.5 %

Procedure:
A suspension of 4-bromo-5-fluoro-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 31E, 490 mg, 1.70 mmol) in EtOH (10.0 mL) was charged with iron powder (473 mg, 8.48 mmol) and then heated to reflux. After 10 min of reflux, the reaction mixture was charged with 1 M of HCl in H2O (2.03 mL, 2.03 mmol) and stirred at reflux for 10 min. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was quenched with NaHCO3 (10 mL) and extracted with DCM (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to an orange solid. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and then concentrated under reduced pressure to yield a bright yellow solid (218 mg, 50%). 1H NMR (CDCl3, 400 MHz): δ 6.38 (d, J=10.9 Hz, 1H) 5.29 (br. s., 2H) 4.22 (s, 2H) 3.14 (s, 3H). MS (ESI): m/z=260.99 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=4)=[C:16]([C:17]#[N:18])[C:9]=23)[CH:7]=1.C(N(CC)CC)C.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>CN(C)C=O>[C:17]([C:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:25][CH3:26])[NH:14][C:15]=1[C:19]1[CH2:20][CH2:21][N:22]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:23][CH:24]=1)#[N:18]
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNCC3)c(C#N)c12
Reactant: CN(C)C(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)N(C)C)CC3)c(C#N)c12
Temperature: 70 °C

Procedure:
To a suspension of Example 248E (125 mg, 0.359 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.30 mL, 2.153 mmol) and 2-chloro-N,N-dimethylacetamide (56 mg, 0.466 mmol) and the mixture was heated at 70° C. for 3 hours. After cooling, the mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with brine and concentrated. The residue was purified by flash chromatography (5-20% methanol in 2:1 ethyl acetate/hexane) to provide the title compound. 1H NMR (400 MHz, DMSO-d6): δ 2.77-2.80 (m, 2H), 2.86 (t, J=5.65 Hz, 2H), 2.95 (s, 3H), 3.11 (s, 3H), 3.37 (q, J=2.75 Hz, 2H), 3.77 (s, 3H), 6.65-6.67 (m, 1H), 7.04-7.12 (m, 3H), 7.15-7.21 (m, 1H), 8.34 (d, J=4.88 Hz, 1H). MS (DCI/NH3) m/z 434 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:27](=[O:28])[CH2:26][Cl:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)CCl
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCl)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloroacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-chloroacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH2:25])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C(N(CC)CC)C.[C:37](O)(=[O:40])[CH2:38][CH3:39]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:27])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH:25][C:37](=[O:40])[CH2:38][CH3:39])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazol-5-yl}methanamine (0.1 g) and triethylamine (0.05 g) were added to dichloromethane (20 mL), followed by the dropwise addition of dichloromethane solution (10 mL) comprising anhydrous propionic acid (0.05 g) under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.1 g, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:24][C:25](OC(C)(C)C)=O)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43]C(OC)O[CH:40]2OC)=[CH:35][CH:34]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:24]1[CH:25]=[CH:40][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:34][CH:35]=2)=[CH:43]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH2:16][OH:17])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(C[C@H](C(=O)N[C@H](CO)Cc1c[nH]cn1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 37 %

Procedure:
According to the procedure described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17 ]-octadeca-11(18),12,14,16-tetraen-9S-yl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-(t-butoxycarbonylamino)-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester was deprotected, and the resultant crude amine salt was condensed with 3-(biphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (produced as described in Example 1(a)) in 1,2-dichloroethane in the presence of trifluoroacetic acid to give in 37% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-[(1H-imidazol-4-yl)methyl]ethyl]succinamic acid benzyl ester as a yellow solid. 1H NMR (CDCl3): δ 7.65-7.59 (m, 4H), 7.53 (d, 2H, J=8.5 Hz), 7.45 (t, 2H, J=7.4 Hz), 7.37-7.26 (m, 7H), 6.95 (s, 1H), 6.70 (t, 1H, J=2.2 Hz), 6.65 (s, 1H), 6.52 (s, 1H), 6.45 (bs, 1H), 5.10 (s, 2H), 5.06-5.02 (m, 1H), 4.13-4.11 (m, 1H), 3.69 (dd, 1H, J=3.9, 11.6 Hz), 3.56 (dd, 1H, J=4.8, 11.8 Hz), 3.42 (dd, 1H, J=5.5, 16.9 Hz), 3.06 (dd, 1H, J=8.8, 16.9 Hz), 2.84 (t, 2H, J=4.8 Hz). Anal. for C33H32N4O4.0.8H2O0 0.15 MTBE: C, 70.34; H, 6.19; N, 9.72. Found: C, 70.51; H, 6.05; N, 10.15 .