Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21].[CH2:33]1[O:37][C:36]2[CH:38]=C(O)[CH:40]=[CH:41][C:35]=2[O:34]1.N1C=CN=C1>C1COCC1>[Br:13][C:14]1[C:15]([CH3:32])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][C:31]1[CH:40]=[CH:41][C:35]2[O:34][CH2:33][O:37][C:36]=2[CH:38]=1)=[O:29])(=[O:21])=[O:22]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)Oc2ccc3c(c2)OCO3)c1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Carbonyldiimidazole (530 mg., 3.26 mmol.) was added to a solution of N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (Example 17) (1.0 g, 2.72 mmol) in dry THF (10 ml). The mixture was stirred at room temperature for 15 minutes. Sesamol (767 mg., 5.44 mmol) and imidazole (185 mg, 2.72 mmol) were added simultaneously. The resulting mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was evaporated. The residue was partitioned between 1N HCl and EtOAc. The organic layer was dried (MgSO4). The solid was filtered and the filtrate concentrated to give a yellow oil which was recrystalized from EtOAc/Et2O/Hexane. N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]-thiophene-3-sulfonamide was obtained as a white powder (494 mg, 37% yield), m.p. 174-176° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:17]O>>[ClH:1].[CH3:17][NH:11][C@H:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 2 h

Procedure:
Dry methanol (200 ml) was saturated with HCl by bubbling in a three-necked round bottom flask and cooled to -10° C. p-Nitrophenylalanine (10.0 g, 47.6 mmol) was added in one portion and left to stir for two hours, then resaturated with HCl. The reaction flask was stoppered with a drying tube and left to stir at room temperature for 18 hours. The solution was evaporated to near dryness on a rotary evaporator and the precipitated product collected in a Buchner funnel. After drying under vacuum at 50° C., the yield of 1 was 10.97 grams (88.3%). A TLC of the free amino ester run in CHCl3 :MeOH (4:1) revealed an Rf =0.85-0.88. 1H NMR (220 MHz, D2O, pH 1.5) δ 8.20 (d, 2, J=10.0), 7.53 (d, 2, J=10.0), 4.55 (t, 1, J=11.0), 3.84 (s, 3), 3.43 (m, 2); CI-MS 225 ((M+1)/z).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:35])[C:6]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:9]3[NH:10][C:11](=[O:28])[CH2:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:25]([CH2:26]O)=[CH:24][N:23]=[N:22]5)[CH:16]=4)=[N:14][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.O=S(Cl)Cl.[CH:40]1([NH2:43])[CH2:42][CH2:41]1>>[CH:40]1([NH:43][CH2:26][C:25]2[N:21]([C:17]3[CH:16]=[C:15]([C:13]4[CH2:12][C:11](=[O:28])[NH:10][C:9]5[CH:29]=[C:30]([C:31]([F:33])([F:34])[F:32])[C:6]([N:5]([CH2:4][CH:1]6[CH2:2][CH2:3]6)[CH3:35])=[CH:7][C:8]=5[N:14]=4)[CH:20]=[CH:19][CH:18]=3)[N:22]=[N:23][CH:24]=2)[CH2:42][CH2:41]1
Reactant: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-(cyclopropylmethyl-methyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78) (145 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (97 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:36]=[CH:37][C:38]([F:39])=[C:33]([F:32])[CH:34]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(F)c(F)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,4-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=95%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:12]1[S:16](=[O:18])(=[O:17])[O:15][CH2:14][CH2:13]1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:14][CH2:13][CH2:12][S:16]([OH:18])(=[O:17])=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: O=S1(=O)CCCO1
Reactant: Fc1ccc2c(c1)CCCN2
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CCCc2cc(F)ccc21
Temperature: 150 °C

Procedure:
To 6,05 g (40 mMol) 6-fluoro-1,2,3,4-tetrahydroquinoline in 20 ml acetone, 5.9 g (48 mMol) of propane sultone dissolved in 20 ml acetone are added dropwise for a period of 40 minutes at 50° to 60° C. After 24 hours of refluxing and again after 48 hours a further 5.9 g of propane sultone are added. After a total of 60 hours of refluxing, the reaction mixture is concentrated by evaporation and the volatile components are removed in high vacuum (0.01 torr) by heating to about 150° C. The residue is recrystallized from 115 ml methanol.
Reaction SMILES: [CH:1](OC)(OC)OC.[Cl:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([NH:22][NH2:23])[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:8][C:9]1[N:21]2[CH:1]=[N:23][N:22]=[C:20]2[CH:19]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(NN)c1
Reactant: COC(OC)OC
Product: CC(C)(C)OC(=O)c1cc(Cl)n2cnnc2c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 43.7 %

Procedure:
Trimethyl orthoformate (100 mL, 903 mmol) was added neat to tert-butyl 2-chloro-6-hydrazinoisonicotinate (10.0 g, 41.0 mmol). The mixture was heated to 85° C. After 5 h, the mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (4.55 g): LC-MS [M+1]=254.1.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Br:21])=[O:30])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Yield: 60.2 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (80 mg, 0.26 mmol) and 2-bromophenylisocyanate (47 μL, 0.38 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70 to 70/30, v/v), gave the desired product (80 mg, 61%). EI-MS (m/z) 508.1, 510.2, 512.2 (M−).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]([CH2:20][C:21](O)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][N:12]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C@H:25]2[C:29]#[N:30])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(CCS(=O)(=O)c1ccccc1)CC(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCS(=O)(=O)c1ccccc1)CC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
[(2-benzenesulfonyl-ethyl)-BOC-amino]-acetic acid (288 mg, 0.84 mmol) and (S)-pyrrolidine-2-carbonitrile (111 mg, 0.84 mmol) were combined in CH2Cl2 (10 mL) at 0° C. EDCI (192 mg, 1.0 mmol) and triethylamine (280 μL, 2.0 mmol) were added, and the reaction stirred for 3 h while warming to r.t. The solution was washed with 0.1 N HCl and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (75% EtOAc/hexanes) gave 188 mg (53%) of (S)-1-[2-(2-benzenesulfonyl-ethyl-BOC-amino)-acetyl]-pyrrolidine-2-carbonitrile as a white foam. 1H NMR (300 MHz, CDCl3): δ 7.91 (t, 2H, J=4.8 Hz), 7.54-7.69 (m, 3H), 4.69-4.79 (m, 1H), 4.17 (t, 1H, J=12.0 Hz), 3.87 (t, 1H, J=12.0 Hz), 3.40-3.77 (m, 6H), 2.12-2.32 (m, 4H), 1.39 (d, 9H, J=5.1 Hz). MS (ES) [m+H]/z calculated for C20H27N3O5S+H 422.17, found 422.10.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:15]([CH2:16][CH2:17]/[C:18]/2=[CH:19]/[CH3:20])[C@H:14]2[C@H:5]1[C@:6]1([CH3:28])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:24])[C@@H:8]([O:25][CH2:26][CH3:27])[CH2:7]1)[CH3:3]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([C@@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:15]([CH2:16][CH2:17][C@@H:18]2[CH2:19][CH3:20])[C@H:14]2[C@H:5]1[C@:6]1([CH3:28])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:24])[C@@H:8]([O:25][CH2:26][CH3:27])[CH2:7]1)[CH3:3]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](N(C)C)C[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)[C@@H](CC)CC[C@@H]32)C[C@@H]1O
Yield: 74.8 %

Procedure:
(Z)-11α-N,N-Dimethylamino-2β-ethoxy-5α-pregn-17(20)-en-3α-ol (585 mg) in ethyl acetate (22 ml) containing 10% Pd-C (400 mg) was stirred under hydrogen. The catalyst was removed by filtration through Kieselguhr and the solvent evaporated in vacuo. Crystallisation of the residue from aqueous methanol gave the title compound (440 mg), m.p. 57°-59° C., [α]D -4.8°.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:28]>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:32]3[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Product: CCN1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CC1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.15 mmol) was used in general procedure 3 with 1-ethylpiperazin (0.77 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(4-ethylpiperazin-1-yl)nicotinamide. MS (Q1) 464.0 (M)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:35]([C:31]2[S:30][CH:34]=[CH:33][N:32]=2)(=[O:37])=[O:36])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 3 from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and thiazole-2-sulfonyl chloride, of Preparation 45 with a reaction time of 3 h. 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 1H), 7.87 (d, 1H), 7.69 (m, 1H), 7.59 (dd, 1H), 7.54 (d, 2H), 7.15 (m, 3H), 6.74 (m, 3H), 6.44 (m, 1H), 4.49 (s, 2H), 4.46 (s, 2H), 4.42 (s, 2H), 1.49 (s, 9H); MS 541 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1)#[N:2].[NH2:16][C:17]1[CH:22]=[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])[C:20]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:18]=1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>ClCCl>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:18]2[CH:19]=[C:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:17]=2[NH:16][C:12]([CH:10]2[CH2:9][NH:8][C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[O:14])[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: N#Cc1ccc2c(c1)NCC(C(=O)O)O2
Reactant: COC(=O)Oc1cc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(C#N)ccc3O2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Yield: 76.5 %

Procedure:
6-Cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (146 mg, 0.72 mmol), tert-butyl 4-(2-amino-5-cyclopentyl-4-methoxycarbonyloxy-phenyl)piperidine-1-carboxylate (300 mg, 0.72 mmol), T3P (570 mg, 533 μL of 50% w/w solution, 1.79 mmol) were dissolved in pyridine (142 mg, 145 μL, 1.79 mmol) and dichloromethane (10 mL) and stirred for 30 min at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) provided tert-butyl-4-[2-[(6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carbonyl)amino]-5-cyclopentyl-4-methoxycarbonyloxy-phenyl]piperidine-1-carboxylate (333 mg, 77% yield). LC/MS m/z 605.6 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(F)c4)noc3N)CC2)c1
Yield: 82.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (601 mg, 1.52 mmol, 82%) was obtained.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1.[CH:23]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[ClH:32].CCO>CC(O)C>[ClH:32].[OH:1][CH:2]([CH2:22][NH:31][CH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1
Reactant: NC1CCCCCCC1
Reactant: O=c1c(-c2ccccc2)coc2cc(OCC3CO3)ccc12
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: O=c1c(-c2ccccc2)coc2cc(OCC(O)CNC3CCCCCCC3)ccc12

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)isoflavone with cyclooctylamine followed by acidification of the resulted free base with HCl/EtOH gave the hydrochloride as light yellow prisms, m.p. 185°-186° (iPrOH).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11](OCC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)n1ccc2c(Cl)ncnc21
Reaction time: 63 h
Yield: 94 %

Procedure:
To a 1 liter round bottom flask equipped with a stir bar, condenser and nitrogen inlet was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 31.0 g, 0.202 mol) and triethyl orthoformate (330 ml, 2.00 mol, 10.0 equiv). The reaction mixture was warmed to reflux to generate a clear solution. The reaction was checked after 63 hours by HPLC. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel flash column chromatography eluted with a 20% to 25% ethyl acetate/hexane (v/v) gradient (TLC conditions: 30% ethyl acetate/hexane) to afford 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3b, 48.56 g, 51.65 g theoretical, 94% yield) as a light yellow oil. For 3b: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.68 (s, 1H), 7.79 (d, 1H, J=3.8 Hz), 6.75 (s, 1H), 6.72 (d, 1H, J=3.8 Hz), 3.68 (dd, 2H, J=9.4, 7.2 Hz), 3.54 (dd, 2H, J=9.4, 7.2 Hz), 1.11 (t, 6H, J=7.2 Hz); C11H14ClN3O2 (MW, 255.70), LCMS (EI) m/e 182/184 (M++H for corresponding 7-formylation product of 1) and 154/156 (M++H for 1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15]([NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(NCc1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide (4.3 g, 12 mmol), benzylamine (1.8 g, 18 mmol), and triethylamine (8.0 mL, 57 mmol) in toluene was refluxed (96 hours) then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (2×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane to yield 3.35 g (72.8%) of the title compound as a white solid, mp 134°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C

Procedure:
3-Fluoro-4-nitrophenol (Fluorochem) (10 g, 64 mmol) was dissolved in butan-2-one (60 ml) and treated with potassium carbonate 16.6 g (120 mmol) at 40° C. for 10 minutes. The resulting suspension was cooled to 0° C., treated with methyl iodide (7.5 ml, 120 mmol), heated to 40° C. for three hours and concentrated in vacuo to 20 ml. The mixture was poured into dichloromethane (35 ml), filtered and the filtrate evaporated to give 3-fluoro-4-nitroanisole, as a white solid (8.0 g, 73%). An analytically pure sample was obtained by recrystallization from aqueous ethanol (4:1); mp 47°-49° C.; ir 1608 cm-1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17]Cl)[CH3:15])[CH2:3]1.O.C(=O)([O-])[O-].[K+].[K+].[N-:26]=[N+:27]=[N-:28].[Na+]>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([CH:8]([CH3:10])[CH3:9])[C@H:4]([O:11][CH2:12][CH2:13][N:14]([CH2:16][CH2:17][N:26]=[N+:27]=[N-:28])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
4.5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chlo roethyl)-N-methylamine were added to a mixture of 40 ml water and 20 ml tetrahydrofuran. 2 g of potassium carbonate and 1 g of sodium azide were added to the mixture. The reaction solution was then stirred at room temperature for 8 hours. The reaction solution was worked up by concentrating to about 30 ml and extracting the aqueous phase with ethyl acetate. After concentration of the ethyl acetate extract, 4.5 g of crude N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-ylo xy)ethyl]-N-(2-azidoethyl)-N-methylamine were obtained, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:31][N:32]=[C:33]=[S:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([CH:28]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([S:21]([NH:22][C:33]([NH:32][CH3:31])=[S:34])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CN=C=S
Reactant: CCOc1cc2c(cc1S(N)(=O)=O)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2
Product: CCOc1cc2c(cc1S(=O)(=O)NC(=S)NC)C(CNC(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman ##STR41## 4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-ethoxychroman is prepared as described in Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-ethoxychroman and methyl isothiocyanate. Melting point: 202° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]([CH3:24])[CH2:9][CH2:10][NH:11][C:12]([C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=O>C1COCC1>[C:14]12([CH2:12][NH:11][CH2:10][CH2:9][CH:8]([OH:7])[CH3:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: CC(O)CCNC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCNCC12CC3CC(CC(C3)C1)C2
Yield: 31 %

Procedure:
To a suspension of LiAlH4 (51 mg, 1.36 mmol) in THF (1.5 mL) was added a solution of N-(3-hydroxybutyl)adamantane-1-carboxamide (170 mg, 0.68 mmol) in THF at 0° C. The mixture was stirred and heated under reflux overnight. The reaction was quenched with H2O (2 mL). The mixture was filtered to give 4-(1-adamantylmethylamino)butan-2-ol (50 mg, 31%). 1H NMR (CD3OD, 400 MHZ): δ=1.12 (d, 3H), 1.58˜1.88 (m, 17H) 2.28 (t, 2H), 2.65 (m, 2H), 3.79 (m, 1H).