Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][C:4]2[C:8]([C:10]3[C:15]([NH:16][C:3]=2[CH:2]=1)=[CH:14][C:13]1[C:17]([C:19]2[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:20]=2[NH:21][C:12]=1[CH:11]=3)=[O:18])=[O:9].COC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(OC)=CC=3)=CC=2C(O)=O)=CC=1.P(=O)(O)(O)O.CO>O>[CH:24]1[CH:25]=[C:19]2[C:17]([C:13]3[C:12]([NH:21][C:20]2=[CH:22][CH:23]=1)=[CH:11][C:10]1[C:8]([C:4]2[C:3]([NH:16][C:15]=1[CH:14]=3)=[CH:2][CH:1]=[CH:6][CH:5]=2)=[O:9])=[O:18]
Reactant: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Agent: COc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(OC)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 113 °C
Reaction time: 0.5 h
Yield: 434 %

Procedure:
To 270 g of polyphosphoric acid (117% phosphoric acid) heated at 85° C. was added 2.5 g of N-[3-(N,N-dimethylaminopropyl)] copper phthalocyanine sulfonamide followed by 13.5 g of 2,9-dichloroquinacridone. The mixture was stirred at 113° C. for 30 minutes, after which 40.5 g of 2,5-di(4-methoxyanilino)terephthalic acid was added. The resultant mixture was heated at 113° C. for five hours. After the melt was cooled to 95° C., the acid strength was adjusted to 113% by the dropwise addition of phosphoric acid. The mixture was slowly poured into 470 g of methanol. The slurry was heated at reflux for two hours, diluted with water and stirred at 60° C. for 30 minutes. The slurry was further diluted with water, after which the solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water (320 g total water), the pH was adjusted to 8.5 with dilute aqueous sodium hydroxide, and 320 g of methanol was added. The resultant slurry was then heated at 120° C. for six hours in a closed system. After the slurry was cooled to 45°-50° C., 4.8 g of wood rosin (as the sodium salt) was added. After the mixture was stirred for 30 minutes, 10.0 g of CaCl2.2H2O (dissolved in water) was added, the slurry was stirred for one hour, and the pH was acidified (if necessary) with phosphoric acid. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 48 g of quinacridone as a deep violet pigment.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.C[Si]([CH:22]=[N+:23]=[N-:24])(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH:22]=[N+:23]=[N-:24])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=CC(=O)c1ccc(Cl)c(Br)c1
Temperature: -5 °C

Procedure:
To a mixture of 3-bromo-4-chlorobenzoic acid (1.51 g, 6.4 mmol, 1.00 eq.) in DCM (25 mL) cooled at −5° C., oxalylchlorid (0.8 mL, 9.6 mmol, 1.50 eq.) and 4 drops of DMF were added. The reaction mixture was warmed to r.t. over 20 hours. The mixture was concentrated in vacuo. The resulting oil was dissolved in THF (50 mL) and cooled to −5° C. (Trimethylsilyl)diazomethane solution (2.0 M in hexanes, 7.2 mL, 14.4 mmol, 2.25 eq.) was added and the mixture was allowed to warm to r.t. over 18 hours. The mixture was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 60 fractions of 45 mL, Heptane to Heptane+20% AcOEt) to yield 1-(3-bromo-4-chloro-phenyl)-2-diazo-ethanone as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[OH:7][CH2:8][C:9]([CH2:11][OH:12])=O.[H][H]>[Ni].CO>[NH:1]([CH:9]([CH2:11][OH:12])[CH2:8][OH:7])[CH:2]([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: O=C(CO)CO
Reactant: [H][H]
Reactant: NC(CO)CO
Agent: [Ni]
Solvent: CO
Product: OCC(CO)NC(CO)CO
Temperature: 25 °C
Yield: 75.7 %

Procedure:
In an autoclave, a mixture of serinol (10.6 g, 0.12 mol), 1,3-dihydroxyacetone (10.4 g, 0.12 mol), and Raney nickel (1 g, wet) in methanol (100 ml) was heated to 65° C. under 250 psi hydrogen pressure for 3 h. The autoclave was cooled to ambient temperature and depressurized. The resulting reaction mixture was filtered to remove the catalyst. The filtrate was evaporated under vacuum to remove ammonia and most of the water. The residue was dissolved in a 1:1 mixture of 2-butanol and tetrahydrofuran, treated with activated carbon, and evaporated to give the bis-adduct 2,2′-iminobis-1,3-propanediol as a viscous oil (15 g, 79%). Assay by GC: 99%.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:12]C1C=CC(C(O)=O)=NC=1.FC1N=C(C(O)=O)C=CC=1>>[F:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([NH:10][NH2:11])=[O:9])=[N:7][CH:2]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: NNC(=O)c1cccc(F)n1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1ccc(F)cn1

Procedure:
5-Fluoro-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 5-fluoro-2-pyridinecarboxylic acid (CAS [107504-08-5], commercially available e.g. from Apollo Scientific or Beta Pharma) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: C[C@H](O)C(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:3]1.C(N(CC)CC)C.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.C1COCC1>[OH:7][C@H:6]1[C@H:2]([NH:1][C:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:3][N:4]([C:8](=[O:21])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)N1C[C@@H](O)[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 96 h
Yield: 61.2 %

Procedure:
1-((3R,4R)-3-Amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (1.0 g) was dissolved in chloroform (30 mL) and THF (10 mL), followed by addition of triethylamine (0.55 mL) and triphenylmethyl chloride (1.4 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=4:1-2:1) to obtain 1-((3R,4R)-3-hydroxy-4-(tritylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (1.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClCCl>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4](=[O:20])/[CH:5]=[C:6](/[C:13]1[CH:18]=[CH:17][C:16]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:15][CH:14]=1)\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccc(C#CCN(C)C)cc1

Procedure:
A solution of (E)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester (0.728 g, 2.2 mmol), dimethyl-prop-2-ynyl-amine (0.56 ml, 6.58 mmol), bis(triphenylphosphine) palladium(II) chloride (0.061 g, 0.088 mmol), copper(I) iodide (1.25 mg, 0.0065 mmol) in dry triethylamine (7 ml) were heated to 100° C. by microwave irradiation for 20 min. To the cooled reaction mixture was added dichloromethane (20 ml) and silica gel Fluka 60 (5 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][Sn:2](Cl)([CH3:4])[CH3:3].C1COCC1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.CCOCC>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Sn:2]([CH3:4])([CH3:3])[CH3:1])=[CH:14][CH:13]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: C[Sn](C)(C)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a 1M solution of trimethyltin chloride in THF (92 ml, 92 mmol) was slowly added a 1M solution of 4-chlorophenylmagnesium bromide in Et2O (92 ml, 92 mmol) over a 40 min period at −10° C. so that the temperature never exceed 0° C. After the addition, the cooling bath was removed and the resulting suspension was stirred at RT for 1 h. A saturated aqueous solution of NH4Cl (14 ml) was added followed by water until complete dissolution of the precipitate. The mixture was transferred into a separating funnel and extracted with Et2O (3×). The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; isocratic elution with cyclohexane) to yield the title compound (24.47 g, 89 mmol, 97%) as a colorless oil. TLC: RF=0.76 (cyclohexane/AcOEt 95:5); HPLC: AtRet=3.25 min; 1H NMR (400 MHz, CDCl3): 0.31 (s, 9H) 7.32-7.36 (m, 2H) 7.41-7.45 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[CH3:8][O-:9].[Na+].[C:11]1([C:17]([CH:19]=O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH3:8][O:9][C:6]1[C:2]([C:3]([NH2:5])=[O:4])=[N:1][CH:19]=[C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=1
Reactant: N#CC(N)C(N)=O
Reactant: C[O-]
Reactant: O=CC(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccccc2)cnc1C(N)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Under argon, 2 g (20 mmol) of 2-amino-2-cyanoacetamide was initially charged in 15 g of methanol. 0.55 g (3 mmol) of sodium methoxide solution (30%) was added and the mixture was stirred at 20° C. for 2 hours. At 0° C., 3.2 g (21 mmol) of phenylglyoxal was added and the mixture was then stirred at 0° C. for 2 hours and concentrated. The product was purified by column chromatography (eluent ethyl acetate/methanol 4/1). This gave 3 g of 3-methoxy-5-phenylpyrazine-2-carboxamide. The yield was 65 percent. Other data concerning the title product was:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:42])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[C:13]([F:32])[CH:12]=3)=[CH:8][C:7](=[O:33])[C:6]=2[C:34]=1[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C=O.CO.O.NN>[NH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:5]3[C:4]([F:42])=[CH:3][C:2]([F:1])=[C:34]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:6]=3[C:7](=[O:33])[CH:8]=2)=[CH:12][C:13]=1[F:32]
Reactant: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Agent: NN
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NCCCN)c(F)c3)cc(=O)c12
Reaction time: 4.3 h

Procedure:
60 mg of Compound 32 was dissolved in 30 ml of a mixed solvent of dimethylformamide and methanol, 0.050 ml of hydrazine monohydrate was added and the mixture was stirred at 60° to 70° C. for 4.3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give Compound 33 which was dissolved in chloroform. A 5.5N hydrochloric acid-isopropylalcohol solution was added, the solvent was distilled off under reduced pressure and the residue was treated with isopropyl ether to form the slurry from which 33.6 mg (67%) of hydrochloride of Compound 33 was obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[C:22]([F:29])[CH:21]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and N-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add 4-Bromo-2-fluorobenzoic acid chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for one hour. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e): 355.1/357.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:29][CH3:30])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[N:7]=3)[CH2:3][CH2:2]1.C1COCC1>CO.[Pd]>[CH:1]1([C:4]2[N:5]([CH2:29][CH3:30])[C:6]3[C:11]([N:12]=2)=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@@H:14]2[CH3:19])[N:9]=[C:8]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[N:7]=3)[CH2:2][CH2:3]1
Reactant: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c(C2CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)nc21
Yield: 73.9 %

Procedure:
A solution of (S)-4-(8-cyclopropyl-9-ethyl-2-(4-nitrophenyl)-9H-purin-6-yl)-3-methylmorpholine (76.0 mg, 0.186 mmol) dissolved in anhydrous methanol (3.0 mL) and anhydrous THF (4.6 mL) was subjected to a continuous flow hydrogenated apparatus (H-Cube: 10% Pd/C cartridge, 1.0 mL/min flow). The crude was concentrated in vacuo and purified by column chromotagraphy (Si-PPC, gradient 20 to 100% ethyl acetate in heptane) to give the desired product as a white solid (52.0 mg, 73.8%). 1H NMR (CDCl3, 500 MHz) δ ppm 8.28 (d, J=8.5 Hz, 2H), 6.73 (d, J=8.6 Hz, 2H), 5.47 (broad s, 1H), 5.17 (broad s, 1H), 4.40 (broad s, 2H), 4.03 (dd, J=11.3 Hz, 3.3 Hz, 1H), 3.89 to 3.77 (m, 2H), 3.68 (td, J=12.0 Hz, 2.8 Hz, 1H), 3.50 (t, J=11.7 Hz, 1H), 2.02 to 1.91 (m, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.33 to 1.22 (m, 2H), 1.20 to 1.10 (m, 2H), 1.06 (dd, J=8.0 Hz, 3.1 Hz, 2H); LC-MS m/z (method A)=379.3 [M+H]+, RT=1.96 min.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(#N)C.O>[N:23]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)ccc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 81B (16 g), azetidine hydrochloride (12.2 g) and triethylamine (21.9 mL) in acetonitrile (500 mL) was stirred for 2 hours, treated with triethylamine (900 mg), stirred for one hour, diluted with water (1.5 L), stirred for 1 hour, and filtered.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.[C:23]([O:27][C:28](OC([O-])=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OC([O-])=O)(=O)[O-]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Agent: O=C([O-])OC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (27.7 g, 94.8 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) in dry methanol (300 mL) was added t-butylpyrocarbonate (25.0 g, 114 mmol). Shortly after the addition of the pyrocarbonate, a clear solution was formed. The solution was stirred at ambient temperature for 1 h, resulting in formation of a white precipitate. The solid was collected by filtration, washed with a 1:1 mixture of diethyl ether:pentane, and dried in vacuo to yield the product as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.CCN(CC)CC.[NH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:30][CH2:29]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et3N (72 μL, 0.52 mmol), and CH2Cl2 (300 μL) under N2, was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 98% CH2Cl2/2% MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=4)[N:17]=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[CH3:32][N:33]([CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl>[CH3:34][N:33]([CH3:32])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][N:41]([C:27]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:18]3[N:17]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([S:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)(=[O:8])=[O:9])=[CH:15][CH:14]=4)[CH:21]=[CH:20][N:19]=3)=[CH:31][CH:30]=2)=[O:29])[CH2:42][CH2:43]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: O=C(O)c1ccc(Nc2nccc(-c3ccc(S(=O)(=O)C4CCOCC4)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCN1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(S(=O)(=O)C5CCOCC5)cc4)n3)cc2)CC1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
4-{4-[4-(Tetrahydropyran-4-sulfonyl)-phenyl]pyrimidin-2-ylamino}benzoic acid 4 (0.26 g, 0.6 mmol) was dissolved in THF (5 mL). To this solution was added 1-(N,N-dimethylaminopropyl)piperazine (0.130 g), EDCI (0.136 g), and HOBt (0.096 g). The mixture was stirred 12 h. The mixture was then diluted with CH2Cl2 (20 mL) and washed with 2% NaOH (aq, 30 mL), water (30 mL), and then brine (30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude solid was subjected to preparative HPLC (20–70 acetonitrile/water gradient, 20 min). The desired fractions were concentrated to remove most of the acetonitrile, and then the aqueous mixture was extracted with CH2Cl2/2% NaOH (aq). The organic layer was dried (Na2SO4), filtered, and concentrated to afford [4-(3-dimethylamino-propyl)piperazin-1-yl]-(4-{4-[4-(tetrahydropyran-4-sulfonyl)phenyl]pyrimidin-2-ylamino}phenyl)methanone 5 (0.079 g, 22%): HPLC Retention Time; 7.93 min. (Method B) M+1=593.3
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][O:10]/[C:11](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)/[C:12]([O:14][CH3:15])=[O:13].O>CN(C)C=O>[CH2:1]([NH:8][C:30](=[O:31])[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17](/[CH:16]=[C:11](\[O:10][CH3:9])/[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
0.6 mL (3.9 mmol) of heptylamine is added to a solution of 1.7 g (3.2 mmol) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate (prepared according to Example 11e) in 10 mL of dimethylformamide and the reaction medium is then placed in a bath preheated to 80° C. After stirring at 80° C. for 3 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 1.1 g (80%) of methyl (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate are obtained in the form of a white solid with a melting point of 93° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.Cl[S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[C:27]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[N:28][C:29]3[C:34]([N:35]=1)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[CH2:21][CH2:20][CH2:19]2)(=[O:15])=[O:14].C(OCC)(=O)C>ClCCl>[CH3:2][N:3]([CH3:4])[S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[C:27]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[N:28][C:29]3[C:34]([N:35]=1)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[CH2:21][CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)Cl)ccc43)nc2c1
Reactant: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)N(C)C)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of dimethylamine hydrochloride (49.66 mg, 0.61 mmol) in dichloromethane (50 mL) was added and triethylamine (102 mg, 1.01 mmol) and stirred for 10 min. Then methyl 3-[6-(chlorosulfonyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (260 mg, 0.51 mmol) in dichloromethane (20 mL) was added dropwise with stirring for 30 min at room temperature. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2%-5% ethyl acetate in petroleum ether to afford methyl 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (240 mg, 91%).