Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)C23CC4CC(CC(C4)C2)C3)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and adamantane-1-carboxylic acid chloride were mixed in methylene chloride. The pH was adjusted to 8.5 with triethylamine and the reaction stirred 10 mins at 25° C. The mixture was flash chromatographed on silica gel (5% Et2O in Et2O in Ch2Cl2CH2CL2) and the title compound obtained by trituration with ethyl acetate: (mp 256°-257° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.C(Cl)(=O)OCC.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27])=[O:10]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: Nc1cccc(C(=O)O)c1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=CC(=O)Nc2cccc(C(=O)O)c2)cc1OC
Reaction time: 2 h
Yield: 50 %

Procedure:
2 Grams of 3,4-dimethoxycinnamic acid were dissolved in a mixture of 20 ml of dry dimethylformamide and 1.5 g of triethylamine. To this solution was added under ice cooling and agitation 1.1 g of ethyl chlorocarbonate and the mixture was then reacted for one hour. To this mixture were added 10 ml of dimethylformamide containing 1.5 g of 3-aminobenzoic acid and the mixture was stirred for 2 hours. After completion of the reaction, the reaction liquid was concentrated approximately to 1/2 volume and poured into an aqueous solution of hydrochloric acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from an equivolume mixture of ethanol and water to obtain a yield of 50% 3-(3',4'-dimethoxycinnamoylamino)-benzoic acid having a melting point of 225°-226° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:37]=[C:36]([N:38]4[CH2:43][CH2:42][N:41]([CH2:44][C:45]5[CH2:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH2:47][C:46]=5[C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=5)[CH2:40][CH2:39]4)[CH:35]=[CH:34][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:30][NH:29][CH2:28]4)=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:74][CH2:75][C:76](=O)[CH2:77][F:78]>ClCCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([C:46]2[CH2:47][C:48]([CH3:52])([CH3:51])[CH2:49][CH2:50][C:45]=2[CH2:44][N:41]2[CH2:42][CH2:43][N:38]([C:36]3[CH:35]=[CH:34][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:30][N:29]([CH:76]([CH2:77][F:78])[CH2:75][F:74])[CH2:28]5)=[C:21]([N+:31]([O-:33])=[O:32])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:37]=3)[CH2:39][CH2:40]2)=[CH:58][CH:57]=1
Reactant: O=C(CF)CF
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CNC5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CN(C(CF)CF)C5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A solution of EXAMPLE 161B (0.118 g), sodium triacetoxyborohydride (0.035 g) and 1,3-difluoropropan-2-one (0.012 g) were stirred together in dichloromethane (1 mL) overnight. The reaction was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted into dichloromethane (30 mL). The organic layer was dried and concentrated. Silica gel chromatography (Reveleris 12 g) eluting with a gradient of 0.5% to 3.5% methanol/dichloromethane over 30 minutes (Flow=36 ml/min) gave the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 11.67 (s, 1H), 11.47-11.21 (m, 1H), 8.85 (s, 1H), 8.55 (d, 1H), 8.03 (d, 1H), 7.80 (dd, 1H), 7.54-7.45 (m, 3H), 7.33 (s, 2H), 7.04 (d, 3H), 6.67 (d, 1H), 6.38 (dd, 1H), 6.20 (d, 1H), 4.43 (dt, 4H), 3.56 (t, 2H), 3.46 (s, 2H), 3.12 (m, 6H), 2.74 (m, 3H), 2.17 (m, 7H), 1.95 (s, 2H), 1.39 (d, 2H), 0.92 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18]O)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:16]([C@@:13]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[CH:17]=[CH2:18]
Reactant: OB(O)c1cncc(Cl)c1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cncc(Cl)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.97 min, m/z=451 (M+1); 1H NMR (CDCl3) 8.68 (d, 1H, J=2 Hz), 8.59 (d, 1H, J=2 Hz), 7.94 (t, 1H, J=2.2 Hz), 7.33-7.27 (m, 4H), 7.04 (ap q, 2H, J=9, 17 Hz), 5.75-5.65 (m, 2H), 5.12-5.02 (m, 2H), 3.03-2.98 (m, 1H), 2.66-2.54 (m, 2H), 2.41-2.17 (m, 3H), 1.56 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O-:27].[Na+]>CO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([O:27][CH3:26])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Temperature: 60 °C

Procedure:
To a suspension of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (EXAMPLE 306 Step B) (34.5 mg, 0.098 mmol) in methanol (1 mL) was added sodium methoxide (56 μL, 25 wt. % in MeOH) dropwise. The mixture was heated at 60° C. for 2 h (the mixture became homogeneous), then was cooled and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography using 1:4 EtOAc:hexane system to give 26 mg of the title compound. Mass spectrum 346.0 (CI, M+1).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:4][F:5].[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>O1CCCC1>[F:5][CH2:4][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[N+:27]([O-:29])=[O:28])[CH2:8][CH2:7]1)[CH2:2][F:1]
Reactant: OCC1CCN(C(CF)CF)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol (0.068 g) in tetrahydrofuran (1 mL) was added sodium hydride (0.056 g) and the reaction stirred for 30 minutes at room temperature. 4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was added in one portion and stirring was continued for 1 hour. The reaction was poured into water (20 mL) and extracted with dichloromethane. The pH of the aqueous layer was adjusted to pH ˜8 and it was extracted with dichloromethane (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:36]=[C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-n2cc(-c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (0.65 g, 2.38 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (0.45 g, 2.38 mmol), N,N-diisopropylethylamine (1.24 mL, 7.14 mmol) and phenylacetylene (0.37 g, 3.57 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 70% yield: mp 175-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.47-7.37 (m, 8H), 6.11 (br s, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.3, 148.7, 137.4, 129.2, 129.0, 128.9, 128.8, 127.8, 126.0, 124.4, 116.7, 44.3, 17.4; MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2F)(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][CH2:40][NH2:41]>C(#N)C>[CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:41][CH2:40][CH2:39][CH:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH3:33])(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Reactant: CN1CCCC1CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2NCCC2CCCN2C)c1C(=O)O

Procedure:
A solution of Example 385I (120 mg, 0.33 mmol), triethylamine (0.24 mL) and N-methyl-2-(2′-aminoethyl)pyrrolidine (217 mg, 1.7 mmol) in acetonitrile (3 mL) was heated to 120° C. in a sealed vial for 2 days, concentrated, and purified using a reverse phase HPLC, giving the desired product, 79 mg, 50.3%. 1H NMR (DMSO-d6) δ 1.08 (t, 3H), 1.28 (t, 3H), 1.60-1.70 (m, 1H), 1.80-2.00 (m, 3H), 2.12-2.30 (m, 2H), 2.53 (q, 2H), 2.68 (s, 3H), 2.90-3.04 (m, 1H), 3.20-3.32 (m, 3H), 3.50-3.60 (m, 1H), 3.90 (q, 2H), 5.98 (br s, 1H), 6.60 (d, 1H), 6.68 (t, 1H), 6.85 (d, 1H), 7.15 (d, 1H), 7.40 (t, 1H), 7.58 (d, 1H), 9.68 (s, 1H), 10.48 (br s, 1H); MS (ESI(+)) m/e 476 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2OCC[O:18]2)=[CH:13][CH:12]=1)O.Cl[Si](C)(C)C.[I-].[Na+].C(#N)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1cccc(C)c1C(O)c1ccc(C2OCCO2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(C)c1Cc1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of (2,6-dimethylphenyl)[4-(1,3-dioxolan-2-yl)phenyl]methanol (7.10 g), chlorotrimethylsilane (10.8 g), sodium iodide (15.0 g) and acetonitrile (50 mL) was stirred at 50° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 7:3 by volume ratio) to give 4-(2,6-dimethylbenzyl)benzaldehyde as pale-yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[S:22][C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=3)[C:17](=[O:30])[CH:16]=2)[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[S:22][C:23]([C:27]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:28])=[C:24]([CH3:26])[N:25]=3)[C:17](=[O:30])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use pyridin-3-ylmethanamine in place of benzylamine to react with 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 47% yield: mp 170-172° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=8.1 Hz, 2H), 8.55 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.37-7.27 (m, 1H), 6.43 (t, J=5.7 Hz, 1H), 6.16 (dd, J=8.1, 2.6 Hz, 1H), 5.96 (d, J=2.6 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.86-0.74 (m, 1H), 0.52-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.9, 162.5, 162.1, 153.7, 152.6, 148.6, 148.3, 136.3, 131.3, 121.7, 104.2, 96.6, 69.1, 41.4, 33.6, 17.3, 7.56, 4.2; MS (ES+) m/z 411.2 (M+1).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12.O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:2]1[CH2:7][CH:6]([C:8]2[N:9]=[C:10]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[S:11][CH:12]=2)[N:5]=[C:4]2[C:19]3[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[CH:22][C:20]=3[O:21][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Cl
Product: COc1ccc2oc3c(c2c1Cl)=NC(c1csc(NC(=O)C(C)C)n1)CC=3Cl
Reaction time: 0.17 h

Procedure:
A mixture of 11G (300 mg, 0.72 mmol) in POCl3 (5 mL) was refluxed for 30 min. After reaction completed, POCl3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 161 mg of product (M11).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[CH2:21][CH2:22]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:36][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)NCCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine gave the title compound.
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][CH2:16][CH2:17][N:18]([CH2:77][CH3:78])[CH2:19][CH2:20][C@@H:21]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41](=[O:69])[C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][CH:51]([C@H:54]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[C:62]4[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=4)[OH:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)(=[O:39])=[O:38])=[CH:33][C:32]=1[S:70]([C:73]([F:76])([F:75])[F:74])(=[O:72])=[O:71])[CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:68][C:65]1[CH:66]=[CH:67][C:62]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[C@H:54]([OH:55])[CH:51]2[CH2:50][CH2:49][N:48]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([NH:40][S:37]([C:34]4[CH:35]=[CH:36][C:31]([NH:30][C@H:21]([CH2:20][CH2:19][N:18]([CH2:77][CH3:78])[CH2:17][CH2:16][OH:15])[CH2:22][S:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[C:32]([S:70]([C:73]([F:74])([F:75])[F:76])(=[O:71])=[O:72])[CH:33]=4)(=[O:38])=[O:39])=[O:69])=[CH:43][CH:44]=3)[CH2:53][CH2:52]2)=[CH:63][CH:64]=1
Reactant: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CCO)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A solution of HCl in dioxane (4M, 11.18 ml, 44.70 mmol) was added slowly to a light yellow solution of N-(4-((R)-4-((2-(tert-butyldimethylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (INTERMEDIATE 66, 2.4 g, 2.24 mmol) in DCM (11.2 ml) at 0° C. Once the addition was complete, the ice bath was removed. The resulting solution was allowed to warm to r.t. and stirred for 1 hour before being concentrated under reduced pressure to half volume and diluted with ethyl acetate. The resulting mixture was washed with sodium bicarbonate (saturated, aqueous) and sodium chloride (saturated, aqueous) before being dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, silica gel, 0→20% methanol in ethyl acetate for 30 min) to provide the title compound (1.64 g, yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([CH2:12]Br)=[CH:11][C:7]=2[CH:6]=1)=[O:4].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[S:9][C:10]([CH2:12][C:17]3[NH:16][CH:20]=[CH:19][N:18]=3)=[CH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2sc(CBr)cc2c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2sc(Cc3ncc[nH]3)cc2c1
Yield: 49.6 %

Procedure:
A mixture of 2-bromomethylbenzo[b]thiophene-5-carboxylic acid methyl ester (1.71 g), imidazole (4.08 g) and sodium bicarbonate (0.55 g) in acetone (50 ml) was heated under reflux for 3 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave first a small amount of starting material followed by product. Evaporation of the product containing fractions gave a solid which was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-(1-imidazolylmethyl)benzo[b]thiophene-5-carboxylic acid methyl ester (0.81 g), m.p. 127°-128°.
Reaction SMILES: Br[C:2]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=1[CH:4]=O.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:24][O:23][C:19]([C:20]1[S:21][C:2]2[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][CH3:15])[C:7]([N+:16]([O-:18])=[O:17])=[CH:6][C:3]=2[CH:4]=1)=[O:22]
Reactant: COC(=O)CS
Reactant: CCOc1c([N+](=O)[O-])cc(C=O)c(Br)c1OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1c([N+](=O)[O-])cc2cc(C(=O)OC)sc2c1OCC
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3,4-diethoxy-5-nitrobenzaldehyde (1.5 g) in N,N-dimethylformamide (5 ml) were added methyl thioglycolate (1.5 g) and triethylamine (2.2 ml) at 0° C. Stirring was continued at room temperature overnight. 1 M HCl was added and the product was extracted with ether. The organic phase was dried with Na2SO4 and evaporated. The crude product was triturated with methanol.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[N:20]2C2CCCCO2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][O:11][CH3:12]>CO>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][CH:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:29][CH3:30])[NH:20]2)=[C:16]([NH2:31])[N:15]=1)[CH2:10][O:11][CH3:12]
Reactant: COCC(C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCC(C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reaction time: 24 h

Procedure:
TFA (7.5 ml) was added to a solution of 2-{[1-methyl-2-(methoxy)ethyl]oxy}-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.7 g, 13.9 mmol) in MeOH (30 ml) with stirring. The mixture was left to stand at room temperature for 1 day. A white solid formed which was filtered off and washed with ethyl acetate. This gave product (3.7 g, 76.1%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH2:15]([NH2:18])[CH:16]=[CH2:17]>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:18][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: C=CCN
Reactant: O=C(O)C1CCc2cc(Cl)ccc2O1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCNC(=O)C1CCc2cc(Cl)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.1 g of 6-chloro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (1A) (Witiak et al. (1971), supra) in 15 ml of thionyl chloride was refluxed for 45 minutes. The excess thionyl chloride then was stripped off and the residual liquid taken up in 50 ml of methylene chloride. To this stirred solution was added dropwise a solution of 2.5 g of 2-propenamine in 10 ml of methylene chloride. The resulting mixture was stirred at room temperature overnight, then was washed with water, dried (MgSO4) and stripped of solvent. Dry column chromatography of the solid product through silica gel, using Solvent No. 3 (a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane) as eluent, followed by recrystallization of the product from ethylene chloride and hexane gave 1, as a pale yellow solid, mp: 112.5°-114° C. Example 2
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15]C3CCCCO3)[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:15])[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-isopropoxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (110 mg, 0.29 mmol) in EtOH (4 mL) was added an aqueous solution of lithium hydroxide (25.2 mg, 0.60 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 30 min and acidified with 1N HCl to pH=4. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (40 mg. Yield: 51.8%). 1H NMR (400 MHz, CDCl3) δ12.2 (s, 1H), 9.38 (s, 1H), 9.08 (s, 1H), 6.64 (3, 1H), 6.46 (s, 1H), 5.29-5.32 (m, 1H), 3.55 (m, 2H), 3.06-3.10 (m, 1H), 2.00-2.02 (m, 1H), 1.29-1.33 (m, 3H). MS (ESI) m/z=267 [M+H]+.