Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(Cl)Cl.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])(O)=O.[Na+]>O>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:27][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:31])[CH3:34]
Reactant: CCOC(=O)CCN
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 3 h

Procedure:
6.4 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)acrylate are initially introduced into 30 ml of methylene chloride. A solution of 3.1 g of ethyl 3-amino-propionate hydrochloride in 12 ml of water is added to this. A solution of 1.7 g of NaHCO3 in 20 ml of water is added dropwise to the two-phase mixture with vigorous stirring. After the dropwise addition is complete, the mixture is stirred for a further 3 hours. The phases are then separated, and the organic phase is washed with water and dried over Na2SO4. After concentration, 7.8 g of the title compound remain. Melting point: 96°-97° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH:10]=[CH:9]2)=[CH:6][C:5](Br)=[CH:4][C:3]=1[S:14]([OH:17])(=[O:16])=[O:15].CO.C(O)(=O)C>[Pd].O>[NH2:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:5]=[CH:4][C:3]=1[S:14]([OH:17])(=[O:15])=[O:16]
Reactant: Nc1c(C2C=CCC2)cc(Br)cc1S(=O)(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(C2CCCC2)cccc1S(=O)(=O)O
Temperature: 50 °C

Procedure:
9.6 g (30.3 mmol) of 2-amino-5-bromo-3-cyclopent-2-en-1-ylbenzenesulphonic acid are placed in a Parr apparatus and 1 g of 10% palladium-on-charcoal, 80 ml of methanol, 10 ml of acetic acid and 50 ml of water are added. The reaction medium is heated to 50° C. under a pressure of 0.35 MPa (50 psi). It is filtered through Celite, the filtrate is concentrated under reduced pressure and the residue thus obtained is crystallized from a methanol/pentane mixture.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O-:18].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[NH:16])[O:18][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 0.08 h

Procedure:
A mixture of 10.7 (0.05 ml) of 5-(4-nitrophenyl)-2-furonitrile and 500 ml of anhydrous methanol was heated on a steam bath until a solution resulted. After slight cooling, a catalytic amount (0.1 g) of powdered sodium methoxide was added with stirring. The solution turned quite dark and in about 5 minutes, solid started to separate. The mixture was allowed to stir for an hour and then was filtered. The solid was washed with anhydrous methanol and air dried. The yield was 10.0 g (81%). Recrystallization from 200 ml of ethyl acetate gave 6.0 g of analytically pure methyl 5-(4-nitrophenyl)-2-furancarboximidate, m.p. 184°-188°.
Reaction SMILES: [C:1]([C:4]1[CH:56]=[CH:55][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30]([NH:32][C@@H:33]([CH2:44][C:45]([O:47]CC4C=CC=CC=4)=[O:46])[C:34]([O:36]CC4C=CC=CC=4)=[O:35])=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2].[H][H]>C(O)(=O)C.O.[OH-].[OH-].[Pd+2].[Pd]>[C:1]([C:4]1[CH:56]=[CH:55][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([CH2:29][C:30]([NH:32][C@@H:33]([CH2:44][C:45]([OH:47])=[O:46])[C:34]([OH:36])=[O:35])=[O:31])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:2])[NH2:3]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)N[C@@H](CC(=O)OCc4ccccc4)C(=O)OCc4ccccc4)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)c1ccc2[nH]c(-c3cc(CC(=O)N[C@@H](CC(=O)O)C(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Reaction time: 10 h
Yield: 52.1 %

Procedure:
Crude dibenzyl(S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinate (18 g) was dissolved in a 1:1 mixture of acetic acid and water (800 mL), assisted by sonication. To this solution was added palladium hydroxide on carbon (Pearlman's catalyst, 20 wt % Pd on a dry weight basis, containing 50% water by weight; 7.0 g). The reaction mixture was pressurized to 30 psi with hydrogen and the suspension was shaken on a Parr apparatus for 10 h. The catalyst was removed by filtration and the solvent was removed in vacuo. Crude (S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinic acid was purified by preparative reverse-phase HPLC to give (S)-2-{2-[5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-yl]acetylamino}succinic acid (7.2 g).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2].[OH:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22]>>[C:1]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:22][CH2:21][CH:20]([OH:19])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:17])=[CH:11][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCOc1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Product: COC(=O)CCCOc1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
The compound was prepared as in Example 5 from 1-(4-(3-carbomethoxypropoxy)phenyl] propan-2-one (6.0 g) and 2-hydroxy-2-phenyl ethanamine (3.29 g) and crystallised from hexane m.p. 60°-76° as a 1:1 mixture of diastereoisomers.
Reaction SMILES: [O:1]1[C@H:5]2[C:6]3[C:11]([CH2:12][C@H:4]2[NH:3]C1=O)=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+]>C(O)C.O>[NH2:3][C@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[OH:1]
Reactant: O=C1N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N[C@H]1Cc2ccccc2[C@H]1O
Yield: 96.3 %

Procedure:
A suspension of (±) cis 3,3a,4,8b-tetrahydroindeno[2,1 -d]oxazol-2-one (Preparation 27) (5.73 g, 0.033 mol) in a mixture of ethanol (100 ml) and water (20 ml) was treated with sodium hydroxide pellets (8.0 g, 0.2 mol). After stirring at room temperature until the sodium hyroxide pellets had dissolved the mixture was heated under reflux in an argon atmosphere for 5 h. The solution was concentrated in vacuo to approximately one quarter the original volume then diluted with brine (50 ml) and extracted into chloroform (3×100 ml). The combined organic extracts were dried over Na2SO4 and then concentrated in vacuo to give a brown solid (4.74 g) which was crystallised from i-propanol-diethyl ether to give the title compound as a colourless solid (3.5 g, 72%) m.p. 104.5°-106° C. Mother liquors afforded a further 0.41 g, m.p. 103.5°-105° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([N+:21]([O-:23])=[O:22])[CH3:20])(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[K+].Cl>C(O)C.O>[C:1]([NH:4][CH:5]([CH2:16][CH2:17][CH2:18][C:19]([CH3:24])([N+:21]([O-:23])=[O:22])[CH3:20])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCCC(C)(C)[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NC(CCCC(C)(C)[N+](=O)[O-])C(=O)O
Temperature: 90 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Diethyl 2-acetylamino-2-(4-methyl-4-nitropentyl)malonate (193.5 g, 558.5 mmol) was dissolved in ethanol (270 ml), and potassium hydroxide (51 g, 781.9 mmol) was dissolved in water (250 ml) and added. The mixture was stirred at 90° C. for 1 h, and potassium hydroxide (51 g, 781.9 mmol) was dissolved in water (250 ml) and added. The mixture was stirred at the same temperature for 2 h. The mixture was cooled to 40° C. and concentrated hydrochloric acid was added to adjust the solution to pH 1.5, which solution was stirred overnight at 80° C. Ethanol was evaporated by concentration under reduced pressure and the residue was ice-cooled. The precipitated crystals were separated, and the obtained slurry was washed with ethyl acetate (200 ml) and dried under reduced pressure to give the objective compound (99.6 g, yield 72%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:24])[CH:23]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:23]1[C:22](=[O:24])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=CC(=O)OC1)C2=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Br)C(=O)OC1)C2=O

Procedure:
tert-Butyl 1-oxo-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (I-16, Step A) (784 mg, 2.33 mmol) was dissolved in DCM (20 mL) and was treated with NBS (498 mg, 2.80 mmol) at 25° C. for 12 hours. The reaction mixture was diluted with DCM (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrates were concentrated and the crude product was purified by column chromatography (ISCO 40 g silica gel column), eluting with 50-100% ethyl acetatehexane gradient to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[OH:20].[C:21](N)(=O)[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[OH:24]>>[OH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]1[O:20][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:7][C:2]=2[N:1]=1
Reactant: NC(=O)c1ccccc1O
Reactant: CCCCCCCCCCCCc1ccc(O)c(N)c1
Product: CCCCCCCCCCCCc1ccc2oc(-c3ccccc3O)nc2c1
Temperature: 220 °C

Procedure:
A three-neck flask fitted with a thermometer, mechanical stirrer and condenser with Dean-Stark trap was charged with 692.5 g. (2.5 moles) of 2-amino-4-dodecylphenol and 411 g. (3.0 moles) of salicylamide. The mixture was heated with stirring to 220° C. After 6 hours of heating, the collection of water in the Dean-Stark trap ceased. At that point, the reaction mixture was cooled to room temperature and about 3 liters of cyclohexane was added. The mixture was then filtered and the filtrate was stripped of volatiles under reduced pressure. The yield of residue was 741.5 g. (2.0 moles). Infrared and nuclear magnetic resonance (nmr) analyses confirmed the structure of the product as 2-(2-hydroxyphenyl)-5-dodecylbenzoxazole, a dark oil. A gas liquid chromatography (glc) analysis indicated the product was 95+% pure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][C:12]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([NH:34][C:14]2[C:15]3[CH2:16][CH2:17][N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][C:10]=3[N:11]=[C:12]([CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:13]=2)=[CH:35][CH:36]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Clc1nc(CN2CCOCC2)nc2c1CCN(Cc1ccccc1)C2
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCN(Cc2ccccc2)C3)cc1
Yield: 25.4 %

Procedure:
The solution of 7-Benzyl-4-chloro-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidine (358 mg, 1 mmol) and 4-tert-butylaniline (179 mg, 1.2 mmol) in acetonitrile (2 mL) was irradiated in microwave at 180° C. for 5 min. Solvent was removed and the residue was dissolved in water, extracted by ethyl acetate, dried over sodium sulfate and purified by column chromatography. Product was obtained as a white foam (120 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: CC(=O)CCl
Product: CC(CCl)=NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-bromo-2-[(2-chloro-1-methylethylidene)hydrazino]-5-(2-pyridyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:15])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC>CN(C)C=O>[OH:15][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][CH:29]=[C:20]2[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([I:16])[CH:18]=3)[C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccc(-c2ccccc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Yield: 89.5 %

Procedure:
4-Aminomethyl-biphenyl-2-ol (80 mg, 0.4 mmol) and 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (110 mg, 0.34 mmol) is stirred in N,N-dimethylformamide (5 mL). After which N,N-dimethylformamide is removed under vacuum and the residue is triturated with MeOH. The precipitate thus formed is collected and washed with MeOH and dried to provide the title compound (151 mg, 89%). MS (ESI): 495.1 (M−1)−1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:20]1[C:19]2[N:18]([N:17]=[C:16]([NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:9]=3)[N:34]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1cccc(CNc2cccn3nc(Cl)nc23)c1
Product: COc1cccc(CNc2cccn3nc(Nc4cccc(N5CCN(C)CC5)c4)nc23)c1

Procedure:
N(8)-(3-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-(4-methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(3-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (11.16 mg, 7%). 1H NMR (400 MHz, CD3OD, δ, ppm): 7.85 (d, J=7.0 Hz, 1H), 7.32 (s, 1H), 7.24 (t, J=15.5, 7.8 Hz, 1H), 7.19-7.09 (m, 2H), 6.99 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 6.75 (t, J=14.2, 7.0 Hz, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.41 (d, J=7.5 Hz, 1H), 4.48 (m, 2H), 3.77 (s, 3H), 3.24 (s, 4H), 2.65 (s, 4H), 2.37 (s, 3H). MS=444 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCNC(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 114.7 %

Procedure:
To a solution of 3-amino-9-ethylcarbazole (500 mg, 2.38 mmol), 4-(tert-butoxycarbonylamino)butyric acid (483 mg, 2.38 mmol) and DIEA (1.246 mL, 7.13 mmol) in DMF (12 mL) was added HATU (1085 mg, 2.85 mmol), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 75% ethyl acetate/hexane) to give crude tert-butyl 4-(9-ethyl-9H-carbazol-3-ylamino)-4-oxobutylcarbamate (1080 mg, 2.73 mmol, 115%) as a pale-yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:28].O1CCOCC1>C(Cl)Cl>[ClH:28].[ClH:28].[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OCCCN3CCCCC3)ccc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc2c(cc1OCCCN1CCCCC1)CCNC2

Procedure:
To a round-bottom flask, equipped with stir bar and septum, is placed 6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1 g, 2.6 mmol), DCM (20 mL) and 4M HCl/dioxane (5 mL). The reaction is allowed to stir at room temperature for 3 h. After this time, the reaction is concentrated, dissolved in MeOH and concentrated again affording 6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride as a white solid (800 mg, 87%). Mass spec hit M+1, 275; LCMS>95% @ 230 nm and ELSD.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:26][CH:27]=[C:28]1[CH:34]=[CH:33][C:32]2[CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=[CH:38][C:31]=2[O:30][CH2:29]1>CO>[Cl:26][CH:27]=[C:28]1[CH:34]=[CH:33][C:32]2[CH:35]=[C:36]([C:39]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:40])[CH:37]=[CH:38][C:31]=2[O:30][CH2:29]1
Reactant: O=C(O)c1ccc2c(c1)C=CC(=CCl)CO2
Reactant: Nc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.3 %

Procedure:
127 mg (0.46 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride and then 39 mg (0.42 mmol) of aniline are added to 100 mg (0.42 mmol) of 3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-carboxylic acid, prepared according to example 63, in solution in 4 ml of methanol, and the medium is stirred at ambient temperature for 3 hours. The methanol is evaporated and the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to give 20 mg (15%) of 3-(chloromethylene)-N-phenyl-2,3-dihydro-1-benzoxepin-7-carboxamide in the form of a pink solid comprising two Z/E isomers as a mixture in an 85/15 ratio; mass (APCI) M+1=312.
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:3]1[C:4](=[O:6])[CH2:5][O:1][C:2]1=[O:7]
Reactant: BrCCCCCBr
Reactant: O=C1COC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COC(=O)C1CCCCCBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of furan-2,4(3H,5H)-dione (500 mg, 5.0 mmol) in THE (10 ml) is added K2CO3 (2.5 g, 18.1 mmol) and the mixture is stirred at room temperature for 3 hours under nitrogen atmosphere. To the reaction mixture is added a solution of 1,5-dibromopentane (5.0 g, 21.7 mmol) in THE (10 ml), slowly over 30 minutes. It is then stirred vigorously at room temperature for one day. The reaction mixture is then partitioned between CH2Cl2 (100 ml) and saturated NH4Cl (50 ml). The organic phase is extracted with CH2Cl2 (3×50 ml), and the combined organic phase is washed with brine (50 ml), dried over MgSO4 and concentrated. The resulting crude product is purified by column chromatography over silica gel eluting with 20% ethyl acetate to give a pure product.
Reaction SMILES: [C:1]([CH2:6][C:7]([CH3:19])([CH3:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([CH3:19])[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:22])[CH3:21]
Reactant: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1

Procedure:
This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 20.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][CH:34]4[C:38](OC)=[O:39])[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[NH:18][N:19]=[C:20]([NH:22][C:23]3[C:32]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=4[N:26]=[C:25]([N:33]4[CH2:37][CH2:36][CH2:35][C@@H:34]4[C:38]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:39])[N:24]=3)[CH:21]=2)[CH2:16][CH2:15]1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)[C@H]1CCCN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCCC2
Reaction time: 0.33 h
Yield: 4.9 %

Procedure:
To a stirred solution of 6-fluoropyridin-3-amine (2.58 g, 23.01 mmol) in THF (40 mL) was added a 2M solution of isopropylmagnesium chloride in THF (11.5 mL, 23 mmol) at 0° C. After 20 min of stirring, to this was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (2.2 g, 5.75 mmol) in THF (10 mL) at 0° C. The reaction mixture was further stirred at RT for 2 h. After completion of reaction it was quenched with saturated ammonium chloride and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layer was treated with brine, dried over Na2SO4 and evaporated under reduced pressure to obtain a crude product, which was purified by column chromatography on 100-200 mesh silica gel using MeOH-DCM (1:10) as eluent to obtain as racemate (0.6 g, 23% yield). The enantiomers were separated by chiral HPLC to afford (R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)-N-(6-fluoropyridin-3-yl)pyrrolidine-2-carboxamide (130 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.60-0.77 (m, 2H), 0.85-0.98 (m, 2H), 1.77-1.90 (m, 6H), 1.91-2.20 (m, 3H), 2.38-2.43 (m, 2H), 2.60-2.80 (m, 3H), 3.59-3.78 (m, 2H), 4.71 (d, 1H), 6.17 (s, 1H), 6.80-6.83 (m, 1H), 6.91 (s, 1H), 7.95 (s, 1H), 8.20 (brs, 1H), 10.90 (brs, 1H).