Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:15]=1.[OH-].[Na+]>CN1CCCC1=O>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[N:15]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1cc(F)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc(C)cc(Oc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 3,4,5-trifluorophenol (33 mg, 0.22 mmol) in 1-methyl-2-pyrrolidone (2 mL) was added at 20° C. under an atmosphere of nitrogen a 55% dispersion of sodium hydride in oil (10 mg, 0.22 mmol). The reaction was stirred for 30 min and then, (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (66 mg, 0.2 mmol) was added. The mixture was heated in a microwave oven to 200° C. for 30 min and then poured onto 1 N aqueous sodium hydroxide solution. The mixture was stirred for 15 min, and the precipitate formed was filtered off, washed with water and dried to yield the title compound (72 mg, 8%) as a pale-brown solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cc(C)cc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cc(C)cc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=1.02 min; [M+H]+=419.11.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:19][N:20]=[C:21]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>CN1C(=O)CCC1.CCOC(C)=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:17])[N:20]([CH3:21])[CH3:19])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of 4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (2.43 g, 10 mmol), EDCI (6.52 g, 34 mmol) and HOBt (4.59 g, 34 mmol) in NMP (20 mL) was stirred at RT for 3 h. A solution of dimethylamine (2.0 M in THF, 15 mL, 30 mmol) was added, and the resulting mixture was stirred at RT for 64 h. Water and EtOAc were then added, and the organic layer was separated and washed twice with a saturated aqueous solution of K2CO3, aqueous HCl (1 M), a saturated aqueous solution of K2CO3, and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give (4-dimethylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.6 g, 59% yield) as a white solid.
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:19][Mg]Cl>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:19][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Product: CCOC(=O)c1cc2c([nH]1)C(Cc1cc(F)cc(Cl)c1)CC2
Yield: 11 %

Procedure:
The title compound was synthesized in two steps. Ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.40 g, 2.23 mmol) was reacted with 3-chloro-5-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 23.0 mL, 5.6 mmol) according to General Procedure 3 to give the exocyclic olefin-containing compound (Z)-ethyl 6-(3-chloro-5-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-20% EtOAc/heptane affording the product as brown solid: 0.055 g (11% yield).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][O:9][C:4]2=[CH:3][CH:2]=1.N1C=CC=CC=1.[Na].N1C=CC=CC=1.O>O>[OH:9][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]#[CH:8]
Reactant: c1ccc2occc2c1
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Product: C#Cc1ccccc1O
Temperature: 25 °C
Yield: 62 %

Procedure:
A 500 ml., three-necked, round-bottomed flask equipped with a thermometer, magnetic stirring bar, reflux condenser, and means for providing a nitrogen atmosphere was charged with a solution of 2,3-benzofuran, 19.0 g. (0.161 mole) in 190 ml. (186 g., 2.35 mole) of pyridine. The reaction system was purged with nitrogen and kept under nitrogen atmosphere throughout the course of reaction. Then freshly cut sodium metal, 11.3 g. (0.490 mole), was added, and the mixture was stirred magnetically and heated with a silicon-oil bath at 190° (reaction mixture temperature 117°) for 4 hours. After cooling to room temperature, the black reaction mixture was treated by successive dropwise addition of 100 ml. of pyridine, 50 ml. of 50% (v/v) pyridine-water, and 100 ml. of water. The resulting red-brown reaction mixture was extracted with 400 ml. of ether. The pyridine-water layer was acidified with excess (750 ml.) of 6 N HCl solution, while the reaction temperature was kept between 20°-30° with an ice-water bath. The acidified mixture was extracted with four 300 ml.-portions of ether. The combined ethereal extracts were washed with 200 ml of 6 N HCl solution and three 200 ml.-portions of water, dried over MgSO4 and concentrated to give 15.3 g. of yellow-brown oil, which was further purified by distillation via a 5" Vigreux column giving rise to 11.7 g. (62% yield) of colorless product, bp12mm 72°-73°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15](F)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:22][CH3:23])=[C:6]([CH:8]([NH:10][C:11]2[CH:16]=[C:15]([N:26]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]3)[CH:14]=[CH:13][C:12]=2[S:18]([CH3:21])(=[O:20])=[O:19])[CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)cc(C(C)Nc2cc(F)ccc2S(C)(=O)=O)c1OC
Reactant: NC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)cc(C(C)Nc2cc(N3CC[C@@H](N)C3)ccc2S(C)(=O)=O)c1OC
Yield: 42.4 %

Procedure:
N-(1-(5-Chloro-2,3-dimethoxyphenyl)ethyl)-5-fluoro-2-(methylsulfonyl)benzenamine (100.0 mg, 0.26 mmol), pyrrolidin-3-amine (86.1 mg, 0.51 mmol), N,N-diisopropylethylamine (133.0 mg, 1.03 mmol) were stirred at 100° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (50.0 mg, 42.8% yield). 1H NMR (400 MHz, CDCl3): δ 7.52 (d, 1H), 6.88 (d, 1H), 6.76 (d, 1H), 6.51 (d, 1H), 6.89 (dd, 1H), 4.84 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.64 (m, 1H), 3.46-2.84 (m, 4H), 3.04 (s, 3H), 2.12 (m, 1H), 2.01 (s, 3H), 1.75, (m, 1H), 1.53 (d, 3H); MS (ESI) m/z: 454.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.Cl.[C:43]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])([CH3:46])([CH3:45])[CH3:44].[H-].[Na+]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[C:43]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][CH2:17][C:15]1[CH:14]=[CH:13][C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]([F:21])([F:19])[F:20])[CH:4]=3)=[CH:9][C:10]=2[CH:16]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: Cc1ccc2sc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of 2-(4-chloro-3-trifluoromethylphenyl)-5-methylbenzo[b]-thiophene (0.746 g, 2.28 mmol) in carbon tetrachloride (23 mL) is added N-bromosuccinimide (0.447 g, 2.51 mmol) and 2,2′-azobisisobuyronitrile (AIBN, 0.075 g, 0.46 mmol). The mixture is stirred at 90° C. overnight, and then concentrated. The residue is passed through a pad of silica gel, which is further rinsed with hexanes. The combined organic solution is concentrated in vacuo. The resulting crude product, 5-bromomethyl-2-(4-chloro-3-trifluoromethylphenyl)benzo[b]thiophene, is dissolved in DMF (2 mL) and added to a pre-stirred suspension of β-alanine t-butyl ester hydrochloride (0.828 g, 4.56 mmol) and sodium hydride (0.365 g, 60% dispersion in mineral oil, 9.12 mmol) in DMF (4 mL). The mixture is stirred at room temperature for 4 hours, quenched with water (1 mL) and concentrated in vacuo. The resulting residue is purified by column chromatography (50% to 70% EtOAc/hexanes) to afford 0.79 g (73%) of 3-{[2-(4-chloro-3-trifluoromethylphenyl)benzo[b]thiophene-5-ylmethyl]amino}propionic acid t-butyl ester as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][C:18]1[NH:23][CH2:22][CH2:21][CH2:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino-3,4,5,6-tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[N:12]([CH2:26][CH2:27][CH3:28])[C:13](=[O:25])[C:14]3[NH:15][C:16]([CH:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:17][C:18]=3[N:19]=2)[CH:5]=1.C[N:31]1CCCN2C1=NCCC2.N>C1COCC1>[CH:20]1([C:16]2[NH:15][C:14]3[C:13](=[O:25])[N:12]([CH2:26][CH2:27][CH3:28])[C:11]([O:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([NH2:31])=[O:2])=[N:19][C:18]=3[N:17]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCn1c(Oc2cccc(C(=O)OC)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Reactant: CN1CCCN2CCCN=C12
Agent: N
Solvent: C1CCOC1
Product: CCCn1c(Oc2cccc(C(N)=O)c2)nc2nc(C3CCCC3)[nH]c2c1=O
Yield: 61.7 %

Procedure:
A mixture of 3-(8-Cyclopentyl-6-oxo-1-propyl-6,7-dihydro-1H-purin-2-yloxy)-benzoic acid methyl ester (0.07 g, 0.17 mmol, 1.0 eq) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (0.034 g, 0.247 m·mol, 1.4 eq) was taken in THF. To this was added Liq.NH3 (˜3 g) through septum in sealed tube at −78° C. and then heated at 50° C. overnight. Crude reaction mixture was purified by preparative TLC to give the product as a white solid (0.04 g) in 60% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([O:27]C1C(Br)=C2C(=CC=1)NC=C2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[C:10]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12]
Reactant: Brc1c(OCc2ccccc2)ccc2[nH]ccc12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)cccc21
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(OCc3ccccc3)ccc21

Procedure:
Using the same procedure as for Intermediate 44 starting from 5-(benzyloxy)-4-bromo-1H-indole, 3.85 g (12.7 mmol) yielded 5.71 g (101%) a dark green crystallizing oil. MS (ESI+) for C21H16BrNO3S m/z 442/444 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14]>C(O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][N:8]=[C:12]([CH2:13][CH3:14])[CH2:11][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(=O)CC
Solvent: CCO
Product: CCC(CC)=NCC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50.2 %

Procedure:
A mixture of glycine tert-butyl ester (Alfa) (0.66 g, 10 mmol) and 3-pentanone (6 g, 70 mmol) in ethanol (6 mL) was heated at 110° C. in a sealed tube for 48 h. The reaction mixture was concentrated and dried in vacuo to give crude (1-ethyl-propylideneamino)-acetic acid tert-butyl ester as a colorless oil (1.0 g). The crude product contains unreacted glycine tert-butyl ester and was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]3=[O:30])[CH:12]=2)[C:7]([CH3:32])([CH3:31])[CH2:6]1)=[O:4]>C(N)(C)C>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][N:16]2[C:17]([CH3:21])([CH3:20])[C:18](=[O:19])[N:14]([C:11]3[CH:12]=[C:13]4[C:8]([C:7]([CH3:32])([CH3:31])[CH2:6][N:5]4[C:3](=[O:4])[CH2:2][NH:5][CH:13]([CH3:8])[CH3:12])=[CH:9][CH:10]=3)[C:15]2=[O:30])[CH:28]=[CH:27][N:26]=1
Reactant: CC1(C)CN(C(=O)CCl)c2cc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)ccc21
Solvent: CC(C)N
Product: CC(C)NCC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Yield: 160.6 %

Procedure:
A solution of 1.426 g of 3-[1-(chloroacetyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage j) of Example 3 in 25 mL of isopropylamine is refluxed for 4 hours. The reaction mixture is then concentrated under reduced pressure and the residue is taken up in 30 mL of water and triturated in 2 mL of diethyl ether. A solid forms, which is filtered off, washed with twice 5 mL of diisopropyl ether and dried to give 1.2 g of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N-isopropylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5](SC)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:4]2=[CH:15][S:16][CH:17]=[C:3]12
Reactant: CSC1=Nc2ccccc2N(C)c2cscc21
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccccc3N(C)c3cscc32)CC1

Procedure:
A solution of 1.2 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine in 6 ml. of N-methylpiperazine is treated with 2-3 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled, and made alkaline with concentrated ammonium hydroxide solution. The precipitate is collected, washed with water and dissolved in chloroform. The chloroform solution is dried and concentrated to an oil, which slowly crystallizes. Recrystallization from ethanol gives yellow crystals, m.p. 83°-85°C.
Reaction SMILES: [Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]1[O:20][C@@H]2C[C@@H]3C[C@H]([C@]2(C)[O:17]1)C3(C)C)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[O:5].Cl.B([O-])OCC(C)C>CO.CCCCCC>[Br:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]([OH:20])[OH:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[O:5]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)COB[O-]
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B(O)O
Reaction time: 8 h
Yield: 72.9 %

Procedure:
To a solution of 2-bromo-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.220 g, 0.44 mmol) in methanol/hexane (1:1) (2.2 mL) were added 1N HCl (1 mL, 1.0 mmol) and isobutyl boronate (0.078 g, 0.76 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was concentrated and purified by reverse phase HPLC to give [(1R)-1-({[(2-bromobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid (0.119 g, 73%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:50][C:51]2[C:52]([C:63](=[O:64])[NH2:65])=[C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:54]=[CH:55][CH:56]=2)=[O:16])[N:13]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)O)cs1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1nc(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To a solution of 2-(N-tert-butylsulfamoyl)thiazole-4-carboxylic acid (0.56 g, 2.1 mmol) in DCM (50 mL) was added HATU (1.41 g, 2.8 mmol) and DIPEA (1.04 ml, 5.6 mmol). The reaction mixture was stirred at room temperature for 1 h and then 3-aminobiphenyl-2-carboxamide (from example 218, 0.3 g, 1.4 mmol) was added. The resulting solution was stirred for an additional 16 h. After this time, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (30% EtOAc in hexane) to provide 2-(N-tert-butylsulfamoyl)-N-(2-carbamoylbiphenyl-3-yl)thiazole-4-carboxamide (0.11 g, 17% yield) as white solid. LCMS Method V: retention time 1.85 min; [M+1]=459.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])=[CH2:3].C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:19]=[O:20])(=[O:12])=[O:11])=[CH2:1]
Reactant: C=C(C)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: C=C(C)c1ccccc1S(=O)(=O)N=C=O
Reaction time: 2 h

Procedure:
To a refluxing mixture of 2-(1-methylethenyl)benzenesulfonamide (2.6 g, 12 mmol) and n-butylisocyanate (1.4 g, 14 mmol) in 20 ml xylenes plus a trace of DABCO (ca. 20 mg) was added liquified phosgene (1.2 ml, 16 mmol) dropwise at 139°. Refluxing was continued for 2 hours, and the solvent was removed in vacuo to give an oil. The infrared spectrum of the oil product exhibited a band at 2220 cm-1 indicating the title compound which was stored as a solution in methylene chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:8][C:7]=12.C(Cl)Cl.C([O-])([O-])=[O:27].[K+].[K+]>C(OC(=O)C)(=O)C.CN(C=O)C.O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:5]2[C:6]3[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:8][C:7]=3[C:2](=[O:27])[NH:3][CH:4]=2)=[CH:17][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)cnc(Cl)c2s1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2c(Oc3ccc(Cl)cc3)c[nH]c(=O)c2s1
Temperature: 60 °C

Procedure:
A solution of Example 311A (200 mg, 0.597 mmol) in acetic anhydride (20 mL) was heated at reflux for 18 hours. The reaction was cooled and poured over ice. The mixture was allowed to stir 1 hour before CH2Cl2 (100 mL) was added. The organic extracts were washed with 1 N NaOH (100 mL), H2O (50 mL) brine (50 mL), dried (Na2SO4), filtered and rotoevaporated to afford a crude brown residue. This residue was directly dissolved in DMF (20 mL) and H2O (3 mL), treated with K2CO3 and warmed to 60° C. for 2 hours. The reaction was allowed to cool to room temperature and then was rotoevaporated. The crude residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate/hexane with a gradient to 50% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CC(C)=O>[CH:19]1([CH2:23][NH:25][CH2:28][CH:30]([OH:32])[CH2:31][NH:25][C:23]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]2)=[CH:22]3)=[O:24])[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]1
Reactant: BrCC1CO1
Reactant: NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NCC(O)CNCC1CCCCC1)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to scheme 7. To an ice-cold solution of 1.0 g (3.0 mmol) of 4-benzylpiperidinyl indole-5-carboxamide in acetone was added 15 mmol of powdered KOH followed by 3.0 mmol of epibromohydrin and the mixture was stirred for 30 min. The mixture was filtered and the solution was evaporated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated. After purification by silica gel column chromatography 435 mg of epoxide was obtained. MS (M+373).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)COCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
() The 2-phenylethoxyacetic acid obtained according to the preceding paragraph was dissoled in 50 ml of tetrahydrofuran and the solution was added dropwise over a period of 10 minutes to a stirred suspension, cooled in an ice-bath, of 1.62 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture was stirred at room temperature for 0.5 hour. The excess lithium aluminum hydride was destroyed by the addition of 1.6 ml of water, then 1.6 ml of 15% aqueous sodium hydroxide solution and finally 5 ml of water. The inorganic solids were removed by filtration, washed well with diethyl ether and the filtrates were evaporated to give 6.50 g (92%) of 2-(2-phenylethoxy)ethanol in the form of an oil which was homogenous according to chromatography. This product can be distilled under reduced pressure; boiling point 140°-142° C./15 mm Hg.