Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>O>[C:9]([CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=2)[CH2:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Nc1cccc(F)n1
Reactant: CC(C)(C)C1CCNC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C1CCN(c2cccc(N)n2)C1
Temperature: 150 °C
Yield: 55.2 %

Procedure:
A suspension of 6-fluoropyridin-2-amine (500 mg, 4.46 mmol), 3-tert-butylpyrrolidine (730 mg, 4.46 mmol) in water (0.5 mL) and triethylamine (0.9 g, 8.92 mmol) was heated to 150° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=20:1) to give 6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-amine (540 mg, 55%) as a brown oil. LC-MS: [M+H]+, 220, tR=1.228 min.
Reaction SMILES: [Li].[CH2:2]([O:4][C:5](=[O:18])[C:6](O)=[CH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9])[CH3:3].[N:19]([O-:21])=O.[Na+].Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][NH2:32]>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:18])[C:6](=[N:32][NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[Cl:24])[CH:7]([N:19]=[O:21])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9])[CH3:3]
Reactant: O=N[O-]
Reactant: NNc1ccccc1Cl
Reactant: CCOC(=O)C(O)=CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NNc1ccccc1Cl)C(N=O)C(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
4-(4-Chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester lithium salt (10 g, 38.37 mmol) was dissolved in acetic acid (400 ml). After the solution was cooled to 10° C. with an ice-water bath, a concentrated aqueous solution of sodium nitrite (2.86 g, 40.29 mmol) was added dropwise, keeping the temperature between 10 and 15° C. The reaction mixture was stirred for another 45 minutes, and 2-chlorophenylhydrazine HCl salt (8.5 g, 46.04 mmol) was added in portions. Stirring was continued for 3 hours. Upon completion of the reaction, the reaction mixture was poured into 600 ml ice-cold water. A yellow solid precipitated and after 2 hours, it was collected, washed with water, and dried to give crude 4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-nitroso-4-oxobutyric acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH2:13]O.CS(Cl)(=O)=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[Na+].[I-]>C1COCC1.O.C(N(CC)CC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]#[C:12][CH2:13][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: OCC#Cc1ccc2ccccc2c1
Reactant: c1c[nH]cn1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C(#Cc1ccc2ccccc2c1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a cooled (0° C.) solution of 3-(2-naphthyl)-2-propyn-1-ol (2.67 g) in THF (100 ml) were added triethylamine (4.1 ml) and methanesulfonyl chloride (1.7 ml) successively. The mixture was stirred at room temperature for 1 hours. Imidazole (3.02 g) and NaI (0.5 g) were added to the mixture and resulting mixture was stirred at 60° C. for 3 hours. To the mixture was added water, and the mixture was concentrated. The residue was extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel, eluting with ethyl acetate, followed by crystallization from cyclohexane to give the titled compound (1.05 g) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9].C[Mg+].[Br-].[CH2:38]1C[O:41]CC1>CCOCC>[CH3:30][C:26]1[N:25]=[C:24]([C:22]([OH:23])=[O:41])[CH:29]=[N:28][CH:27]=1.[OH:1][C:2]([CH3:38])([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:19]3)[CH2:12]1)[CH2:20]2)=[O:9]
Reactant: CC(=O)COc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2cncc(C)n2)(C4)C3)c1
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: Cc1cncc(C(=O)NC23CC4CC(CC(NC(=O)c5cccc(OCC(C)(C)O)c5)(C4)C2)C3)n1
Product: Cc1cncc(C(=O)O)n1

Procedure:
Reaction of 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-oxo-propoxy)-benzoyl-amino]-adamantan-1-yl}-amide with MeMgBr in THF or ether at 0° C. could yield the title compound, 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-hydroxy-2-methylpropoxy)-benzoylamino]-adamantan-1-yl}-amide.
Reaction SMILES: [C:1]([O-:7])(=O)[CH2:2][C:3]([CH3:5])=[O:4].[Li+].C(N(CC)CC)C.[CH2:16]([NH:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:17][CH3:18].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClC(Cl)C>[CH:21]1([CH2:20][N:19]([CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:23][CH2:22]1
Reactant: CCCNCC1CC1
Reactant: CC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCCN(CC1CC1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A stirred mixture of lithium acetoacetate (scheme 2: (G)) (1.00 g, 9.26 mmoles), triethylamine (2.58 mL, 18.5 mmoles), and n-propylcyclopropylmethyl amine (scheme 2: (E)) (1.32 mL, 9.26 mmoles) in dry dichloroethane (60 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) (2.36g, 9.26 mmoles). The mixture was stirred overnight at room temperature, and then acidified (pH˜1) with 1M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over MgSO4. Concentration in vacuo and purification by silica gel chromatography (30% ethyl acetate/hexane) gave 900 mg of a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=1)=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[S:21])=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][CH3:28]>CO>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[S:21][CH:2]=[C:3]([C:5]3[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:6]=3)[N:22]=2)=[CH:18][C:17]=1[O:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCOc1cc(C(N)=S)ccc1OC
Reactant: COC(=O)c1ccc(C(=O)CBr)o1
Solvent: CO
Product: CCCOc1cc(-c2nc(-c3ccc(C(=O)OC)o3)cs2)ccc1OC
Yield: 79.2 %

Procedure:
To a solution of 877 mg of 5-(2-bromoacetyl)-2-methoxycarbonylfuran in 40 ml of methanol was added 800 mg of 4-methoxy-3-propoxythiobenzamide, and the mixture was refluxed for 1 hour. The reaction mixture was concentrated approximately ¼, then added diethyl ether. After cooling the solution, a precipitate was collected by filtration and dried to obtain 1.05 g of 2-(4-methoxy-3-propoxyphenyl)-4-(5-methoxycarbonyl-2-furyl)thiazole as a brown powder. mp. 141.0-142.0° C.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine 1.9 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride, 4 ml of triethylamine and 0.2 g of 4-(dimethylamino)pyridine in 60 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is poured into ice water and the separated organic layer washed with 50 ml each of water, 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and the solvent removed to give a residue. The residue is chromatographed on a silica gel column using 1:4 ethyl acetatehexane to give 1.8 g of the desired product as a solid, m.p. 68°-71° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]2[CH:25]=[C:24]([CH2:23][CH:20]3[CH2:19][CH2:18][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:22][CH2:21]3)[CH:29]=[CH:28][CH:27]=2)[CH:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B(O)O)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cc(C#N)ccn3)c2)CC1
Temperature: 140 °C
Yield: 56.5 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (416 mg, 3 mmol) was added {3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}boronic acid (958 mg, 3.00 mmol) followed by K2CO3 (1,244 mg, 9.00 mmol) and Pd(Ph3P)4 (139 mg, 0.120 mmol) in 1,4-dioxane (15 mL) and water (5 mL). The mixture was heated in a microwave for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 mL). The combined organic layers were filtered, evaporated on Glas-Col, redissolved in hexane/DCM 4 mL (3/1), loaded onto Redisep gel column (40 g) and purified with the Combiflash chromatograph to afford 640 mg (57%) of the title compound. LC-MS m/z 378 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16](=O)[C:17](=[C:24]2[S:27]CS2)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:38][NH2:39]>C(O)C>[CH2:30]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[C:10]([F:29])=[C:11]([C:16]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:24]([SH:27])[NH:38][N:39]=2)[C:12]([F:15])=[CH:13][CH:14]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(C(=C1SCS1)c1ccncc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1-c1n[nH]c(S)c1-c1ccncc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(3-Dibenzylamino-2,6-difluoro-phenyl)-2-[1,3]dithietan-2-ylidene-2-pyridin-4-yl-ethanone (1.26 g, 2.44 mmol) was suspended in absolute ethanol (10 mL). Hydrazine monohydrate (0.473 mL, 9.755 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated under reduced pressure, taken up with toluene (2×20 mL) and evaporated to dryness. The crude product (1.35 g) was used in the following step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:9]1[C:10]2[C:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][C:8]1=2
Reactant: OB(O)c1ccccc1
Reactant: Cn1c2c(c3cccc(Br)c31)C(=O)NCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1c2c(c3cccc(-c4ccccc4)c31)C(=O)NCC2
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (200 mg), phenylboronic acid (131 mg), tetrakis(triphenylphosphine)palladium (0) (11 mg) and 2N sodium carbonate (5 ml) in DME (10 ml) was heated at reflux for 3 h. The cooled mixture was diluted with 2N sodium carbonate (50 ml) and extracted with dichloromethane (3 100 ml). The combined organic extracts were concentrated in vacuo and the residue was purified by FCC eluting with System A (100:8:1) to give a solid (180 mg) which was triturated with ether (20 ml) to give the title compound (160 mg), m.p. 242°-245°.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:12])[CH:3]=1.C(OC(=O)C)(=O)C.ClCCl.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=2[OH:12])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc(F)c(F)cc1O
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(CNC(=O)c2cc(F)c(F)cc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution 4,5-difluoro-2-hydroxybenzoic acid (1 g, 6 mmol, US0061666246) in pyridine (2 mL) was added acetic anhydride (0.8 mL, 7 mol) and the mixture was stirred at room temperature for 2 hr. To this added 10% HCl (10 mL) and extracted the acetate intermediate with ethyl acetate. The ethyl acetate was evaporated and the residue taken up in dichloromethane (10 mL). To this solution added oxalyl chloride (1 mL) and few drops of dimethylformamide and stirred for 1 hr. The solvent was removed and the acid chloride was re-dissolved in dichloromethane (10 mL) and added slowly to dichloromethane solution (10 mL) of p-methoxybenzylamine (0.855 mL, 6.5 mmol). The reaction mixture after 2 hr showed new peak by HPLC and complete disappearance of the starting material. The dichloromethane was removed and the residue dissolved in methanol and to it added 10% aqueous NaOH solution (3 mL) and mixture stirred for 1 hr. The methanol was removed and the residue acidified and extracted with ethyl acetate. The ethyl acetate layer was dried, filtered and evaporated to yield 1.5 g (85%) of N-(4-methoxybenzyl)-4,5-difluoro-2-hydroxybenzamide as a white solid. RP-HPLC: 2.70 min; ES-MS (M+H)+=294; 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1), 7.4 (d, 2), 6.8 (d, 2), 6.6 (dd, 1), 4.6 (s, 2), 3.8 (s, 3).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14]>C(#N)C>[Cl:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[NH:2][NH2:3]
Reactant: NN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
59 g of hydrazine hydrate was dissolved in 712 ml of acetonitrile at room temperature under an atmosphere of nitrogen. A solution obtained by dissolving 46.3 g of 1,2-dichloro-4-nitrobenzene in 71 g of acetonitrile was added dropwisely to the obtained solution. After the addition had been completed, the obtained mixture was subjected to reflux by heat for 4 hours, and the reaction solution was concentrated. 500 g of water was added to the concentrate, and the produced crystals were filtered off. 200 g of acetonitrile was then added to the crystals, and the obtained mixture was subjected to reflux by heat for 30 minutes and then cooled with ice to room temperature. The produced crystals were filtered off (yield: 27 g).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[N:28]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:34][C:33]([F:36])([F:35])[C:29]1[N:30]=[C:31]([N:10]2[CH2:11][CH2:12][CH:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][CH2:3]3)[CH2:8][CH2:9]2)[CH:32]=[CH:27][N:28]=1
Reactant: FC(F)(F)c1nccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccnc(C(F)(F)F)n3)CC2)CC1
Temperature: 70 °C

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (28.5 mg, 0.11 mmol) and cesium carbonate (106 mg, 0.32 mmol) were stirred in NMP (0.5 ml) and the 4-bromo-2-(trifluoromethyl)pyrimidine (12 mg, 0.053 mmol) was added. The mixture was heated at 70° C. for 2 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([Cl:12])[C:4]=1[CH:13]1[CH2:20][N:16]2[CH2:17][CH2:18][N:19]=[C:15]2[CH2:14]1.[H][H]>O.[Ni]>[BrH:1].[NH2:9][C:8]1[C:3]([Cl:2])=[C:4]([CH:13]2[CH2:20][N:16]3[CH2:17][CH2:18][N:19]=[C:15]3[CH2:14]2)[C:5]([Cl:12])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: Br
Solvent: O
Product: Nc1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl

Procedure:
A solution of 6-(2,6-dichloro-3-nitrophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[1,2-a]imidazole hydrobromide (2.3 g.) in water (70 ml.) is shaken with hydrogen in the presence of a Raney nickel catalyst (0.5 g.) at laboratory temperature and atmospheric pressure until uptake of hydrogen ceases. The mixture is filtered, the filtrate is evaporated to dryness and the residue is dissolved in hot ethanol (200 ml.). The solution is concentrated to 20 ml. by distillation and then cooled and filtered. There is thus obtained as solid residue 6-(3-amino-2,6-dichlorophenyl)-2,3,6,7-tetrahydro-5-H-pyrrolo-[1,2-a]imidazole hydrobromide, m.p. 275°-277° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.C(N)CCCCCC.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55](OC3C=CC=CC=3)=[CH:54][CH:53]=2)C)=CC=1)C(O)=O)C>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([CH3:15])([C:17](=[O:19])[NH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Agent: CCCCCCCN
Product: CCCCCCCCNC(=O)C(C)(C)Oc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and heptylamine via the same procedure used for the preparation of (2S, 1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H33NO5 [M+H]+: 380.
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([OH:16])[CH2:8][CH2:7]1)=O.[OH-].[Na+]>CO.O.C(Cl)Cl>[NH2:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:9]([OH:16])[CH2:8][CH2:7]1
Reactant: O=C(N[C@H]1CC[C@H](O)c2ccccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N[C@H]1CC[C@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
To a grey solution of Intermediate 5a (5.55 g, 21.4 mmol) in MeOH (50 mL), NaOH (1.28 g, 32.1 mmol) in water (15 mL) was added, and the mixture stirred at room temperature for 3 days. NaOH (1.28 g, 32.1 mmol) was further added and the brown solution was stirred for 5 h. The solution was applied directly to an SCX-2 column, washing with MeOH and eluting with 2M NH3 in MeOH, and concentrated under vacuum to leave a grey solid. The solid was suspended in DCM (50 mL) with sonication, then filtered and dried under vacuum to leave a pale grey solid (2.93 g, 84%). 1H NMR (400 MHz, d6-DMSO): 1.41-1.64 (2H, m), 2.02-2.13 (2H, m), 3.82 (1H, dd), 4.55 (1H, dd), 5.08 (1H, br s), 7.13-7.22 (2H, m), 7.35-7.49 (2H, m).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH:12][C:13](=[O:21])[O:14]C3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[S:41][C:42]1[CH:43]=[C:44]([NH:45][C:13]([NH:12][C:11]2[N:7]([C:3]3[CH:2]=[C:1]([CH3:26])[CH:6]=[CH:5][CH:4]=3)[N:8]=[C:9]([C:22]([F:25])([F:24])[F:23])[CH:10]=2)=[O:21])[CH:46]=[CH:47][CH:48]=1.[C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]([NH:12][C:13](=[O:14])[NH2:33])=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:2]=1
Reactant: Cc1cccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4cccc(C)c4)c3)c2cc1OC
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2NC(N)=O)c1
Yield: 160 %

Procedure:
The title compound was prepared from the carbamate from Example 338A (108 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.30 mmol) using the procedure in Example 115C to give 14346,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (137 mg, 0.24 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.52-7.25 (m, 9H), 6.86 (s, 1H), 3.98 (s, 6H), 2.41 (s, 3H); LC-MS (ESI) m/z 581 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C1CCCCC1.ClCCl>[CH2:16]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a mixture of carbazole (0.87 g, 5 mmoles) in tetrahydrofuran (THF), NaH (0.24 g, 10 mmoles) was slowly added. The mixture was stirred for 1 hour, obtaining a solution. Benzyl bromide (0.89 ml, 7.5 mmoles) was then added dropwise, and the reaction mixture was stirred for 5 hours at room temperature. The reaction was quenched with ice water and THF was evaporated under reduced pressure. The mixture was extracted with ethyl ether (3×5 mL) and the organic phases were collected and combined, dried over MgSO4 and evaporated under reduced pressure. The solid obtained was triturated with n-hexane (10 mL), filtered and used without further purification. The compound obtained is a white solid with melting point of 123° C. and Rf=0.44 in cyclohexane/dichloromethane 4/1.