Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].C[N+](C)(C)[CH2:16][C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:5]1=[O:13])([CH3:3])=[CH2:2]
Reactant: Cc1cccc2scc(C[N+](C)(C)C)c12
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
1-isopropenylbenzimidazolone (0.5 g, 2.9 mmol) in DMA (8 mL) was added and trimethyl-(4-methyl-benzo[b]thiophen-3-ylmethyl)-ammonium; iodide (1.0 g, 2.9 mmol) and K2CO3 (0.80 g, 5.74 mmol). The reaction mixture was heated to 120° C. for 15 min in a microwave and then 150° C. for another 5 min. The mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 0.7 g of the desired product as a white solid
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1)#[N:26]>>[OH:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[CH:17][C:16]([OH:18])=[CH:15][CH:14]=2)[N:33]([C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[N:34]=1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: N#Cc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: N#Cc1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 7 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-cyanophenylhydrazine hydrochloride (0.085 g, 0.5 mmol) to give 0.012 g of product as a yellow solid MS (APCI) m/z 343 (M−.).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:27]([Cl:42])=[CH:26][N:25]=1.Cl.O1CCOCC1>COCCO>[CH2:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:24]3[N:29]=[C:28]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:27]([Cl:42])=[CH:26][N:25]=3)=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=2[NH:7][C:8](=[O:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1N)CN(Cc1ccccc1)CC(=O)N2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CN(Cc1ccccc1)CC(=O)N2
Temperature: 90 °C

Procedure:
To a solution of 6-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (75 mg, 0.25 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.25 mmol) in 2-methoxyethanol (2 mL) was added 4N HCl-dioxane (0.20 mL). The mixture was heated to 90° C. for two hours whereupon LCMS showed complete consumption of the aniline. After being cooled to room temperature, triethylamine was added to pH 9 and the crude product was purified by preparative tlc (7% MeOH-DCM) to afford N-{(1R,2R)-2-[2-(4-benzyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a light brown foam; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.02 (s, 2H), 7.35 (m, 5H), 7.10 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 3.65 (s, 2H), 3.60 (s, 2H), 3.26 (s, 2H), 2.89 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 601 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:30]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N+:27]([O-:29])=[O:28])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:30])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccc(Cl)cc3)cc21
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chlorophenylmercapto)-butoxy]-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:15]3[C:14]4[CH:16]=[C:17]([C:20]#[N:21])[N:18]=[CH:19][C:13]=4[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:11]=3[N:10]=[CH:9][CH:8]=2)[CH2:3]1.[Cl:30]N1C(=O)CCC1=O>C(#N)C.C(O)(C)C>[Cl:30][C:8]1[CH:9]=[N:10][C:11]2[N:12]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]3[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=3[C:15]=2[C:7]=1[N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)ccnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](O)C3)c(Cl)cnc21
Temperature: 35 °C
Reaction time: 5 h

Procedure:
A mixture of (S)-4-(3-hydroxypyrrolidin-1-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (140 mg, 0.34 mmol) and N-chlorosuccinimide (137 mg, 1.02 mmol) in acetonitrile (1.3 mL) and isopropyl alcohol (0.4 mL) was stirred at 35° C. for 5 hours. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate (1 mL), diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid, which was used in the next step without any further purification (100 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13](OCC)([O:16]CC)[C:14]#[CH:15])[CH3:11]>C(#N)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:12][CH2:10][CH3:11])=[O:16]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: Clc1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C#Cc1cc(Cl)ccc1Br
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 55.2 %

Procedure:
A suspension of 1-bromo-4-chloro-2-iodobenzene (5.4 g, 17.0 mmol), 3,3,3-triethoxyprop-1-yne (4.4 g, 25.6 mmol), copper(I) iodide (976 mg, 5.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (1.19 g, 1.7 mmol) in ACN (60 mL) was degassed and backfilled with argon. The resulting mixture was treated with TEA (22.0 mL, 157.9 mmol). The reaction flask was capped with a septum and stirred at 23° C. After 90 minutes, the reaction was diluted with EtOAc (300 mL) and washed with water (150 mL). The aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, concentrated in vacuo, dissolved in EtOH (50 mL) and water (5 mL) and then treated with p-toluenesulfonic acid monohydrate (5 mg). After stirring at 23° C. for 60 minutes, the solution was concentrated, dissolved in diethyl ether (300 mL) and washed with saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo affording 2.7 g of ethyl 3-(2-bromo-5-chlorophenyl)propiolate.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]([C:25]([F:28])([F:27])[F:26])=[CH:19][C:20](OCC)=[O:21])=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[NH:17][C:15]2=[S:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(NC(=S)Nc1ccc(Cl)c(C(=O)OC(C)C)c1)C(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=S)ccc1Cl

Procedure:
using isopropyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-trifluoromethylvinyl]thioureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-5-[3,6-dihydro-4-trifluoromethyl-6-oxo-2-thioxo-1(2H)-pyrimidinyl]-benzoate,
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11]C3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=[CH:4][C:3]=2[O:2]1.[C:27]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[C:42]([F:43])=[CH:41][N:40]=[C:39](Cl)[N:38]=2)[CH2:32][CH2:31]1)([OH:29])=[O:28].C1COC2C=CC(N)=CC=2O1>>[C:27]([CH:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]2[C:42]([F:43])=[CH:41][N:40]=[C:39]([NH:11][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:10][CH2:1][O:2][C:3]=4[CH:4]=3)[N:38]=2)[CH2:32][CH2:31]1)([OH:29])=[O:28]
Reactant: O=C(O)C1CCC(Nc2nc(Cl)ncc2F)CC1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Nc1ccc2c(c1)OCCO2
Product: O=C(O)C1CCC(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)CC1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, N4-(4-carboxycyclohexyl)-2-chloro-5-fluoro-4-pyrimidineamine and 3,4-ethylenedioxyaniline were reacted to yield N4-(4-carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.62 (d, 1H, J=4.2 Hz), 7.31 (d, 1H, J=2.4 Hz), 6.84 (dd, 1H, J=2.4 and 8.7 Hz), 6.70 (d, 1H, J=8.7 Hz), 4.23-4.18 (m, 4H), 3.99-4.08 (m, 1H), 2.59 (t, 1H, J=3.9 Hz), 2.16-2.09 (m, 2H), 1.91-1.84 (m, 2H), 1.78-1.57 (m, 4H); 19F NMR (CD3OD): −48152; LCMS: ret. time: 19.31 min.; purity: 96%; MS (m/e): 389 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(C(F)(F)F)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 81.1 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 81.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[O:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[O:33][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=5)=[CH:30][CH:31]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 95.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (24 mg, 0.085 mmol), 5-(3-chlorophenyl)-2-furoic acid (9.5 mg, 0.043 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.085 mmol), HOBT (12 mg, 0.085 mmol) and DIPEA (15 μl, 0.085 mmol) in DMF (4 ml) were stirred at room temperature for 4 h. The DMF was evaporated under vacuum and the residue partitioned between ethyl acetate and water. The organic fraction was concentrated under vacuum and the residue purfied by preparative HPLC to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-5-(3-chlorophenyl)-2-furamide (20 mg, 95%). NMR; δH [2H6]—DMSO 10.25,(1H, s), 8.64,(1H, t), 8.11,(1H, t), 7.96-7.94,(3H, m), 7.75,(1H, dd), 7.66,(1H, d), 7.52,(1H, t), 7.49-7.44,(3H, m), 7.39,(1H, d), 7.34-7.31,(2H, m), 3.18,(2H, t), 2.23,(3H, s), 1.06,(1H, m), 0.45,(2H, m), 0.26,(2H, m). LCMS: retention time 3.88 min, MH+485.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Yield: 73.6 %

Procedure:
A solution of 1.50 g (5.14 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxymethyl-phenyl)-piperidine-1-carboxylate, 1.73 g (6.16 mmol) of triphenylchloromethane and 674 mg (6.68 mmol) of triethylamine in 20 ml of methylene chloride was stirred at room temperature for 5 hours. For the working-up, the reaction mixture was washed with 10 ml of water and 10 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The crude product was chromatographed on silica gel using a 95:5 mixture of toluene and ethyl acetate as the eluent. There were obtained 2.08 g (77.5% of theory) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate as a colourless foam; MS: 567 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH:12]=[C:13]([C:15]([OH:17])=O)[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[NH2:23].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[F:20][C:21]([F:34])([F:35])[CH:22]([NH:23][C:15]([C:13]1[O:14][C:10]2[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:19]=[CH:18][C:11]=2[CH:12]=1)=[O:17])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)O)oc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 6-(tert-butoxycarbonyl)-1-benzofuran-2-carboxylic acid (350 mg, 1.33 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (357 mg, 1.46 mmol) in N,N-dimethylformamide (5 ml) was admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (304 mg, 1.46 mmol) and stirred in a closed vessel at 50° C. overnight. The cooled reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat. sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. This leaves 453 mg as a mixture of the tert-butyl ester and of the free acid, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14](Cl)[N:13]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][NH:18]2)=[C:14]([NH:1][C@@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[N:13]=1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(N[C@H]2CCc3ccccc32)c2nc[nH]c2n1
Yield: 79.6 %

Procedure:
(S)-(+)-1-Aminoindane (266.0 mg, 2.0 mmol), 2,6-dichloropurine (380 mg, 2.0 mmol) and N,N-diisopropylethylamine (380 μL, 2.2 mmol), were dissolved in Ethanol (4.0 mL) and reacted in a microwave at 120° C. for 600 s. A yellow solid formed which was filtered, washed with ethanol (20 mL) and dried to give the title compound 0.455 g, 80% yield.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:14]2[CH:15]=[C:16]([C:19](Cl)=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10]1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([CH:39]=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:42]2[N:38]([C:39]([C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:12]=[C:11]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[O:10][C:9](=[O:8])[C:14]=4[CH:15]=3)=[O:20])=[C:40]([CH3:47])[C:41]=2[O:45][CH3:46])[CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1c(C)cn2cc(OCc3ccccc3)ccc12
Reactant: O=C(Cl)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2cc(OCc3ccccc3)ccc12
Reaction time: 2 h
Yield: 71.9 %

Procedure:
10 ml (71.8 mmol) of triethylamine and 15 g (52.7 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride are added portionwise, at ambient temperature and under nitrogen, to the solution of 12.8 g (47.9 mmol) of 6-(benzyloxy)-1-methoxy-2-methylindolizine in 160 ml of dichloromethane. The reaction medium is stirred for 2 hours and is then filtered. The solid obtained is washed with dichloromethane and then with diisopropyl ether and dried. 17.8 g (83%) of an orange powder are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[CH:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCCCCC.C(O)C>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@@:8]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COC(=O)C2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)CC2C)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(COC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Yield: 40.5 %

Procedure:
1-Benzyl 3-(4-methoxyphenyl)methyl (3RS,4SR)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-1,3-dicarboxylate obtained in Example 2h (7.2 g, 14.5 mmol) was optically resolved repeatedly by HPLC(CHIRALPAK AD-H (2 cm diameter×25 cm), elution solvent: hexane/ethanol=85/15, flow rate: 8-10 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time (2.92 g, yield: 40.5%).
Reaction SMILES: [NH2:1][OH:2].Cl.NO.[OH-].[K+].CS[C:10](=[N:20][CH3:21])[N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12]>CO>[CH2:13]([N:11]([CH3:12])[C:10]([NH:20][CH3:21])=[N:1][OH:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN=C(SC)N(C)Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CNC(=NO)N(C)Cc1ccccc1
Reaction time: 4 h
Yield: 1.2 %

Procedure:
A 100 ml. solution of hydroxylamine generated from hydroxylamine hydrochloride (5.86 g., 0.088 mol) and potassium hydroxide (4.59 g., 0.088 mol) was cooled to 0°. To this was added a 25 ml. methanol solution of S-methyl-N-benzyl-N,N'-dimethylisothiourea (3.53 g., 0.017 mol) over a 10 minute period. The mixture was allowed to stir for 4 hours. Methanol was then removed by evaporation and the residue redissolved in methylene chloride. After two washes with 100 ml. quantities of water, the organic layer was extracted with 20 ml. 1N hydrochloric acid. The aqueous layer was then made basic to pH 9 and extracted with methylene chloride. The organic layer was dried, evaporated, and resulted in 0.100 g. of an oil. The oil was separated into its components using high pressure liquid chromatography and 40 mg. (1.2% yield) of pure 1-benzyl-1,3-dimethyl-2-hydroxyguanidine was isolated. It had thin layer chromatographic and NMR properties identical to those of an authentic sample.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8](=[O:10])C)[CH:4]=[N:3]1.[Br:11]N1C(=O)CCC1=O>C1COCC1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:11][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[CH:8]=[O:10]
Reactant: CC(=O)c1cnn(C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cn1ncc(C=O)c1CBr
Yield: 82.7 %

Procedure:
To a stirred solution of 1-(1,5-dimethyl-1H-pyrazol-4-yl)ethanone (471 mg, 3.42 mmol) in THF (13 ml) was added N-bromosuccinimide (637 mg, 3.58 mmol) and benzoyl peroxide (41 mg, 0.17 mmol) at room temperature under nitrogen, then the resulting mixture was refluxed for 20 h. After cooling, the reaction mixture was evaporated to remove the solvents. The residue was chromatographed on a column of silica gel eluting with ethyl acetate-hexane (1:1) gave the title compound as white solid (574 mg, 78% yield). 1H NMR (270 MHz, CDCl3) 2.47 (3H, s), 3.91 (3H, s), 4.87 (2H, s), 7.83 (1H, s). MS (ESI) m/z: 217 (M+H)+.
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([N:20]2C(=O)C3=CC=CC=C3C2=O)=[N:11]1)[CH3:5].O.NN>O>[CH2:31]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:20])=[N:11]1)[CH3:32]
Reactant: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To 70 ml of ethyl alcohol was added 3.50 g of the 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole. The mixture was added with 85% hydrazine hydrate under cooling with ice and stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was removed under reduced pressure. The residue thus obtained was added with 20 m1 of water and extracted with chloroform. The chloroform layer was extracted with 2N hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to 10 with potassium carbonate, and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and filtered. The filtrate was removed under reduced pressure to give 2.03 g of 1-(3-diethylaminopropyl)-3-amino-4 -chloroindazole having the following analytical values in a yield of 85%.