Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])[C@H:16]2[C@H:7]1[C@:8]1([CH3:30])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:28])[C@@H:10]([OH:29])[CH2:9]1.[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH:34]=O>C(O)C.C(=O)([O-])O.[Na+]>[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][NH:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])[C@H:16]2[C@H:7]1[C@:8]1([CH3:30])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:28])[C@@H:10]([OH:29])[CH2:9]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Reactant: CC(C)(C)CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)(C)C)C[C@]12C
Reaction time: 18 h
Yield: 126.2 %

Procedure:
Sodium cyanoborohydride (1.5 g) was added to a mixture of methyl 11α-amino-2β,3α-dihydroxy-5α-androstane-17β-carboxylate (760 mg) and 3,3-dimethyl-butyraldehyde (700 mg) in ethanol (30 ml). The mixture was stirred for 18 h, diluted with 5% sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The extract was washed with water, dried and evaporated to give a foam (1.18 g) which was purified by preparation t.l.c. in ethyl acetate/0.88 ammonia (50:1) to give the title compound (565 mg) as a foam, [α]D +22.1°, νmax 1725 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1SC2C=CC(O)=CC=2N=1.[C:23]1([CH:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:30]2[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32](=[O:40])[C:31]2=[O:41])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C2C(=CC=CC=2)C(=O)C1=O>>[C:42]1([CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]2[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32]([OH:40])([C:9]3[C:8]([OH:11])=[CH:7][C:3]4[O:4][CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)[C:31]2=[O:41])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(F)c21
Agent: Cc1nc2cc(O)ccc2s1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 1A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 2-methylbenzo[d]thiazol-5-ol, and 1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione to replace isatin, 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (83%) as a colourless solid: mp 209-211° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.43-7.27 (m, 11H), 7.01 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.61 (dd, J=8.8, 8.8 Hz, 1H), 6.21 (s, 1H), 6.16 (d, J=7.9 Hz, 1H), 4.25-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.2, 157.9 (d, 1JC-F=248 Hz), 147.1, 145.0 (d, 3JC-F=8.7 Hz), 142.7, 137.7 (d, 2JC-F=30.9 Hz), 135.4, 130.1 (d, 3JC-F=8.7 Hz), 128.4 (d, 3JC-F=13.9 Hz), 128.3 (d, 3JC-F=8.4 Hz), 127.5 (d, 3JC-F=11.9 Hz), 119.4, 117.9 (d, 2JC-F=18.9 Hz), 116.1, 109.3 (d, 2JC-F=20.3 Hz), 107.2 (d, 4JC-F=2.1 Hz), 103.1, 73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 506.0 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH2:36]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:37][CH3:38]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Reactant: CCCBr
Product: CCCOc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with propyl bromide
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][N:11]3[C:14](=[O:25])[C:15]([NH:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][N:20]=4)=[CH:16][CH:17]=[C:10]3[C:9]2=[O:26])=CC=1>FC(F)(F)C(O)=O>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15]2[C:14](=[O:25])[N:11]3[CH2:12][CH2:13][NH:8][C:9](=[O:26])[C:10]3=[CH:17][CH:16]=2)=[N:20][CH:21]=1
Reactant: COc1ccc(CN2CCn3c(ccc(Nc4ccncn4)c3=O)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1ccc(Nc1ccncn1)c2=O
Temperature: 25 °C

Procedure:
A solution of 2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione (5, 0.3 g, 0.79 mmol) in trifluoroacetic acid (5 mL) was heated at 90° C. for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was neutralized with saturated solution of sodium bicarbonate and the compound was extracted in 10% methanol in ethyl acetate. The organic layer was separated, dried over sodium sulphate, concentrated under reduced pressure and the residue obtained was purified via column chromatography (silica, methanol/dichloromethane=10%) to afford 7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione (Cpd. No. 1) as a beige solid. Yield: 0.12 g, 59%; MS (ESI) m/z 258 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.79-8.64 (m, 2H), 8.48 (s, 1H), 8.38 (d, J=5.9 Hz, 1H), 7.41 (dd, J=6.0, 1.3 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 4.23-4.16 (m, 2H), 3.55-3.48 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:11][CH2:10][CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:14])[CH3:13]
Reactant: OCC=Cc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC=Cc1ccc(Br)cc1
Yield: 88.2 %

Procedure:
3-(4-Bromophenyl)prop-2-en1-ol (2.13 g) (see example 1) was reacted with acetic anhydride (1.2 g) in the usual manner to give 3-(4-bromophenyl)prop-2-enyl acetate (2.25 g) NMR 1H: 7.35(2H,d), 7.08(2H,d), 6.52(1H,d), 6.10(1H,dt), 4.65(2H,d), 2.1(3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[SH:12][CH2:13][C:14]([OH:16])=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:16])[CH2:13][S:12][C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CS
Solvent: CCN(CC)CC
Product: O=C1CSC(=S)N1c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 6.12 g. (0.03 m.) of 3,4-dichlorophenyl isothiocyanate, 2.8 ml. (3.68 g., 0.04 m.) of mercaptoacetic acid and a few drops of triethylamine is heated in a pressure bottle at 110°-130°C. for 2 hours. The cooled reaction mixture is filtered to give 3-(3',4'-dichlorophenyl)-rhodanine, m.p. 176°-178°C.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(O)C>[CH3:50][N:51]([CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1
Reactant: CCCCNC
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Solvent: CCO
Product: CCCCN(C)c1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 73 %

Procedure:
A solution of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g) and N-methylbutylamine (0.2 g) in ethanol (10 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-dilute hydrochloric acid. The organic layer was washed with water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.26 g, 73%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[NH:29]1[C:30]2[C:26](=[CH:25][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 49.2 %

Procedure:
Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxyindole (55 mg, 0.41 mmol). The crude product was purified by chromatography on alumina, eluting with methanol/ethyl acetate/methylene chloride (5/45/50) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (70 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH2:21][CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[C:15](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14](=[O:20])[CH:13]3[CH2:21][CH3:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-2-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one (180 mg, 0.52 mmol) in DMF (1 mL) was added N,N-dimethylformamide dimethyl acetal (1 mL). The resulting mixture was heated to 110° C. for 2 h after which the reaction mixture was concentrated under reduced pressure to give the desired product as a brown oil. This crude product was directly taken to the next reaction without any further purification. Retention time (min)=2.365 min, Method [1], MS (ESI) 370 (M-NMe2+OH+H).
Reaction SMILES: C[O:2][C:3]([CH:5]([N:9]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]([NH:19][C:20](=[O:22])[CH3:21])[C:10]1=[O:23])[CH:6]([CH3:8])[CH3:7])=[O:4]>CO.[Pd]>[C:20]([NH:19][C@H:11]([C:10]([NH:9][C@H:5]([C:3]([OH:4])=[O:2])[CH:6]([CH3:7])[CH3:8])=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)C(C(C)C)N1C(=O)C(NC(C)=O)C1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonyl-2-methylpropyl)-3-acetylamino-4-phenylazetidin-2-one (230 mg.) was subjected to hydrogenolysis at 50° C. in methanol (20 ml.) in the presence of a 10% Pd-C (310 mg.) under a hydrogen pressure of one atmosphere. The reaction was completed in 18 hours. The same after-treatment as in Example 1 was followed to give methyl ester of N-acetylphenylalanylvaline (220 mg., yield: 95.5%).
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:4]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:3]1.C(O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[NH:6][C@@H:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:4]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cccc(C3CCC3)c2)C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N[C@H]1Cc1cccc(C2CCC2)c1
Yield: 90.4 %

Procedure:
According to example 82, 1.87 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-cyclobutylbenzyl)-4-morpholinecarboxylate was treated with 3.1 mL of TFA in 30 mL of CH2Cl2 for 4 h. Neutralization with 8 mL of Et3N and work-up in the usual manner gave a light yellow residue. Purification of the crude material by flash chromatography on 85 g of silica gel (8:2 hexane:EtOAc) afforded 1.35 g (91%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-cyclobutylbenzyl)morpholine as a thick, transparent semi-solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([C:20]1[N:21]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:22]=[CH:23][C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])[NH:12]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH2:12][C@@H:11]([C:20]1[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=2)(=[O:34])=[O:33])[CH:22]=[CH:23][C:24]=1[C:25]([OH:27])=[O:26])[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)OC(C)(C)C)c2[C@@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2[C@H](N)CCOCc2ccccc2)cc1
Temperature: 40 °C

Procedure:
An orange solution of (R)-tert-butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-1-tosyl-1H-pyrrole-3-carboxylate (504c, 5.85 g, 10.00 mmol) in DCM (15 mL) was treated with TFA (15 mL, 202 mmol) and heated at 40° C. for 2 h. The TFA and DCM was removed in vacuo affording (R)-2-(1-amino-3-(benzyloxy)propyl)-1-tosyl-1H-pyrrole-3-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (724d) as a dark orange viscous oil which was used for the next step without purification. m/z (ESI, +ve) 429.2 (M+1)′.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:18]=[C:17]([C:19](O)=[O:20])[N:16]([CH3:22])[N:15]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:18]=[C:17]([C:19]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:20])[N:16]([CH3:22])[N:15]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cncc(F)c2)sc1-c1cc(C(=O)O)n(C)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(-c2cncc(F)c2)sc1-c1cc(C(=O)NS(C)(=O)=O)n(C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-[2-(5-Fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-5-carboxylic acid (0.08 g, 0.25 mmol) and methanesulphonamide (0.024 g, 0.25 mmol) were initially charged in ice-cooled dichloromethane (10 ml). 4-Dimethylaminopyridine (0.006 g, 0.05 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.053 g, 0.275 mmol) were added. The reaction mixture was stirred at 0° C. for 2 h and then at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (dichloromethane/ethyl acetate eluent). This gave 0.074 g (72% of theory) of 3-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-N-(methylsulphonyl)-1H-pyrazole-5-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (190 mg, 0.67 mmol) and benzoyl isocyanate (220 mg, 1.3 mmol) are mixed in 3.0 mL of DCM and the mixture is stirred at 50° C. for 2 hrs and room temperature for 16 hrs. Then the solvent is removed and the residue is suspended in 3.0 mL of EtOH. K2CO3 (160 mg, 1.1 mmol) is added and the mixture is heated at 70° C. for 30 min. Then the solvent is removed and the residue is partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer is separated and extracted with DCM (2×50 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (10 mL) and the solid formed is filtered, washed again with EtOAc (2×10 mL) and dried to give 158 mg of 6-(5-bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2C#N)CC1
Temperature: 80 °C
Yield: 44.9 %

Procedure:
To a solution of 4-amino-2-fluoro-5-nitrobenzonitrile (132 mg, 0.730 mmol) and tert-butyl piperazine-1-carboxylate (136 mg, 0.730 mmol) in DMF (3 ml) was added triethylamine (0.102 ml, 0.730 mmol). The mixture was heated to 80° C. in a Microwave reactor for 50 min., cooled to r.t., purified by prep-HPLC to afford tert-butyl 4-(5-amino-2-cyano-4-nitrophenyl)piperazine-1-carboxylate (120 mg, 0.328 mmol, 44.9% yield). 1H-NMR (CD3OD, 500 MHz): δ 8.42 (1H, s), 6.45 (1H, s), 3.65-3.61 (4H, m), 3.28-3.25 (4H, m), 1.51 (9H, s). m/e (M+H): 348.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)C(C)c1ccc2nc(-c3ccccc3Cl)oc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2nc(-c3ccccc3Cl)oc2c1

Procedure:
The ethyl 2-(2-o-chlorophenyl-6-benzoxazolyl)propionate from (a) was stirred with sodium hydroxide solution (50 ml.) After 11/2 hours the solution was evaporated to dryness. Acidification and re-crystallisation from ether gave 2-(2-o-chlorophenyl-6-benzoxazolyl)-propionic acid, m.p. 108° - 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(OCC)(=O)C>O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NCCN1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCNCCN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 35.2 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (5.812 g, 15 mmol) obtained from step 6 of Example 1 and 2-morpholin-4-yl-ethylamine (10.725 g, 82.5 mmol) was dissolved in water bath at 30° C. and stirred for 5.5 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (100 ml) and saturated brine (100 ml), stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-methyl-5-[3-(2-morpholin-4-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10a (2.238 g, yield 87%) as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[C:20]1([CH2:26][CH2:27][CH:28]=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:28]([OH:29])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: O=CCCc1ccccc1
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Agent: [Li]CCCC
Product: N#Cc1ccc(C(C(O)CCc2ccccc2)n2cncn2)cc1

Procedure:
1-[1-(4-cyanophenyl)-2-hydroxy-4-phenylbutyl]-1,2,4-triazole is prepared by the method described in Example 1 starting from 1-(4-cyanobenzyl)-1,2,4-triazole (2.0 g, 0.0108 mol), n-BuLi (0.0108 mol) and 3-phenylpropionaldehyde (1.74 g, 0.013 mol). The product is purified by flash chromatography.
Reaction SMILES: [CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.IC.N1[CH2:29]CCN2CCCCCC=12>CN(C=O)C>[CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[N:15]2[CH3:29])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NC1CCCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.14 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (1,2,3,4-tetrahydronaphthalen-1-yl)amide were reacted with 23.85 mg (0.168 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) at RT. Yield: 12 mg (23%), M+H+: 371.42.
Reaction SMILES: C[Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[N+:16]([O-:23])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:24](=O)([O-])[O-].[K+].[K+]>CCOCC.O1CCCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH:22]3[C:17]([CH3:24])([CH2:18][CH2:19][CH2:20][CH2:21]3)[N:16]([OH:23])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C2C[N+]([O-])=C3CCCCC32)cc1OC
Reactant: O=C([O-])[O-]
Agent: C[Mg]Br
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2CN(O)C3(C)CCCCC23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A volume of 10 ml of 3M methyl magnesium bromide in ether was added over a period of two minutes to a stirred solution of 4.12 g (0.015 mole) of 3,3a,4,5,6,7-hexahydro-3-(3,4-dimethoxyphenyl)-2H-indole 1-oxide in 25 ml of tetrahydrofuran. The warm solution was stirred for 1/2 hour at room temperature and then added cautiously to 50 ml of ice water. The mixture was stirred for 5 minutes and solid potassium carbonate was added to saturate. The mixture was extracted into 200 ml of ether and the extract was decanted, dried over K2CO3, filtered and concentrated to ca 50 ml volume. The separated crystals were filtered and washed with ether; wt. 2.5 g, mp 147°-149° C. A second crop weighing 0.6 g was obtained for a total weight of 3.1 g (71% yield). The product was recrystallized from ethyl acetate to give pure white crystals melting at 147°-149° C.