Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[S:39]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:26][CH2:27][N:28]([S:39]([CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])(=[O:41])=[O:40])[CH2:29][CH:30]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nc(C(C)C)no5)CC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (95 mg, 0.223 mmol) and triethylamine (0.078 ml, 0.558 mmol) in CH2Cl2 (2 ml) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (67.2 mg, 0.335 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt overnight. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 50% EtOAc) to afford methyl 4-(4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (68 mg, 0.107 mmol, 48% yield) as an off white solid. 1H NMR (500 MHz, chloroform-d) δ 7.64 (d, J=1.9 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.5, 1.9 Hz, 1H), 6.07 (dt, J=3.2, 1.8 Hz, 1H), 5.45 (tt, J=7.0, 3.6 Hz, 1H), 4.03 (q, J=2.8 Hz, 2H), 3.90-3.82 (m, 2H), 3.69 (s, 3H), 3.65 (ddd, J=13.5, 7.2, 4.1 Hz, 2H), 3.58 (t, J=5.6 Hz, 2H), 3.12-3.06 (m, 2H), 2.90 (spt, J=6.9 Hz, 1H), 2.67 (s, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.23-2.12 (m, 4H), 2.06 (dtd, J=13.8, 7.1, 4.0 Hz, 2H), 1.29 (d, J=6.9 Hz, 6H). LCMS (m/z)=590 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[S:6](F)(=[O:15])([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C>C(O)CCC>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:6]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:15])=[O:7]
Reactant: COCCN
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COCCNS(=O)(=O)c1ccc(N)cc1
Yield: 65.4 %

Procedure:
A mixture of 2-methoxyethylamine (859 mg, 11.4 mmol), sulphanilyl fluoride (1.0 g, 5.71 mmol) and triethylamine (1.72 g, 22.9 mmol) in 1-butanol (15 ml) was heated at reflux for 18 hours. The mixture was allowed to cool and the volatiles were removed by evaporation. The residue was purified by chromatography eluting with ethyl acetate/hexane (50:50) increasing in polarity to (70:30) to give the title compound (860 mg, 65%). NMR: 2.78 (q, 2H), 3.15 (s, 3H), 3.25 (t, 2H), 5.87 (s, 2H), 6.58 (d, 2H), 7.10 (t, 1H), 7.40 (d, 2H); m/z 231.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[C:11]1([N:17]=[CH:18]OCC)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[OH:1][C:2]1[C:3]([CH:18]=[N:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CCOC=Nc1ccccc1
Solvent: CCO
Product: Oc1ccc2[nH]ncc2c1C=Nc1ccccc1
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
A round bottomed flask containing a mixture of 5-hydroxy-1H-indazole (28.5 g) and ethyl N-phenylformimidate (35 g) was submerged rapidly in an oil bath pre-heated to 175° C. and the mixture stirred at 160-180° C. for 30 minutes, the ethanol produced in the reaction being removed by distillation. The cooled mixture was then treated with boiling methanol (500 ml) and the resultant brown solid collected by filtration, washed with methanol (100 ml) and dried to give 5-hydroxy-4-(N-phenyliminomethyl)-1H-indazole (32 g) as a yellow solid. The solid was dissolved in hydrochloric acid (5 M; 500 ml) and heated at 50-60° C. with stirring for 2 hours. The mixture was diluted with water (500 ml) and extracted with ethyl acetate (2×500 ml). The combined extracts were washed with water (500 ml), dried over magnesium sulphate and the solvent evaporated under reduced pressure to give 5-hydroxy-1H-indazole-4-carboxaldehyde (15.48 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Br.Br[CH:7]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]1=O.[OH-].[Na+]>>[O:3]1[C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:1]=[C:2]1[NH2:4]
Reactant: NC(N)=O
Reactant: O=C1CCNCCC1Br
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2c(o1)CCNCC2
Temperature: 70 °C
Reaction time: 24 h
Yield: 23.8 %

Procedure:
6.6 g urea was added to 6 g 5-bromo-azepan-4-one hydrobromide. The mixture was stirred 24 h at 70° C. The reaction was basified with 4 N NaOH and extracted with chloroform and ethylacetate. The combined organic layers were evaporated to yield 800 mg of the desired product.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:17][CH:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>>[O:9]=[C:7]([NH:17][CH:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC(C)N
Reactant: CC(=O)SC/C(=C/c1ccccc1)C(=O)O
Product: COC(=O)CC(C)NC(=O)/C(=C\c1ccccc1)CSC(C)=O

Procedure:
The (E)-2-acetylthiomethyl-3-phenylpropenoic acid described in Example 1 (step C) is coupled with methyl 3-(RS)-aminobutanoate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([CH3:24])=[CH:22][S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([CH3:24])=[CH:22][S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+](C1N=C2N(C=1)CC(OCC1C=CC(OCC(N3CCC(=O)CC3)=O)=CC=1)CO2)([O-])=O.C([O:36][C:37](=[O:60])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][CH:48]2[CH2:53][O:52][C:51]3=[N:54][C:55]([N+:57]([O-:59])=[O:58])=[CH:56][N:50]3[CH2:49]2)=[CH:42][CH:41]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[N+:57]([C:55]1[N:54]=[C:51]2[N:50]([CH:56]=1)[CH2:49][CH:48]([O:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][C:37]([OH:60])=[O:36])=[CH:45][CH:44]=1)[CH2:53][O:52]2)([O-:59])=[O:58]
Reactant: CC(C)(C)OC(=O)COc1ccc(COC2COc3nc([N+](=O)[O-])cn3C2)cc1
Agent: O=C1CCN(C(=O)COc2ccc(COC3COc4nc([N+](=O)[O-])cn4C3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(COC2COc3nc([N+](=O)[O-])cn3C2)cc1

Procedure:
1-{2-[4-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetyl}-piperidin-4-one. A solution of [4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxylmethyl)-phenoxy]-acetic acid tert-butyl ester (130 mg, 0.32 mmol) in TFA (1.0 mL) and dichloromethane (2.0 mL) was stirred at room temperature for 1.5 h. Solvent was evaporated to give [4-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetic acid. To a solution of the above acid in dichloromethane (6.0 mL) under N2 was added diisopropylethylamine (0.20 mL), 4-piperidone hydrochloride monohydrate (98 mg, 0.64 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), 1-hydrobenzotriazole (52 mg, 0.38 mmol). The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane, washed with saturated NaHCO3 and 1 N HCl solution, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by preparative TLC plates (5% MeOH in dichloromethane) to give the title product as oil (28.0 mg, 20%). ESI MS m/z 431 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 4.77 (s, 2H), 4.67-4.53 (m, 3H), 4.32 (d, J=12.0 Hz, 1H), 4.15-4.07 (m, 3H), 3.91-3.85 (m, 4H), 2.50-2.45 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C([O:17][C:18](=[O:55])[CH2:19][CH:20]([NH:24][C:25](=[O:54])[CH:26]([S:34]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21](O)=[O:22])(C)(C)C>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:21](=[O:22])[CH:20]([NH:24][C:25](=[O:54])[CH:26]([SH:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:19][C:18]([OH:55])=[O:17])=[CH:5]1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C(Cc1ccccc1)SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCc1c[nH]c2ccccc12
Product: O=C(O)CC(NC(=O)C(S)Cc1ccccc1)C(=O)NCCc1c[nH]c2ccccc12
Yield: 39 %

Procedure:
This compound was prepared by condensing tryptamine with 2-(3-phenyl-2-tritylsulfanyl-propionylamino)-succinic acid 4-tert-butyl ester using the same coupling conditions as previously described. Deprotection and purification then provided the title compound (39%): (Pos FAB) 440 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:3]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([NH:39][CH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)=[O:38])=[O:31].[CH2:47](I)[CH3:48]>>[CH2:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:41]([CH2:40][NH:39][C:37]([C@H:33]2[CH2:34][CH2:35][CH2:36][N:32]2[C:30]([C@@H:3]2[C@@H:2]([OH:1])[C@@H:6]([OH:7])[CH2:5][N:4]2[C:8](=[O:29])[CH2:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:31])=[O:38])[CH2:42]1)[CH3:48]
Reactant: CCI
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1[C@@H](O)[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCN1CCC[C@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2[C@@H](O)[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Example 77, using (2R)-1-{(2S,3R,4S)-3,4-dihydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidyl-methyl)pyrrolidine-2-carboxamide and ethyl iodide. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=2)[CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:12]=[C:11]([C:33]([F:36])([F:35])[F:34])[CH:10]=1)=[O:8].[CH3:41]OC1C=CC=CC=1CNC(C1N(C2C=C(C=CC=2)CNCCN(C)C(=O)OC(C)(C)C)N=C(C(F)(F)F)C=1)=O.COC1C=CC=CC=1CNC(C1N(C2C=CC=C(CNC)C=2)N=C(C(F)(F)F)C=1)=O>>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=2)[CH2:17][N:18]([CH3:29])[CH2:19][CH2:20][N:21]([CH3:41])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[N:12]=[C:11]([C:33]([F:35])([F:34])[F:36])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN(C)CCNC(=O)OC(C)(C)C)c1
Agent: CNCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC)c1
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(CN(C)CCN(C)C(=O)OC(C)(C)C)c1

Procedure:
The title compound 142 (103 mg, 0.179 mmol, 46% yield) was isolated as white foam following the procedure described for the synthesis of compound 59 (scheme 8, example 6, step 7), except using 141 (205 mg, 0.3855 mmol) in place of 58. LRMS (ESI): (calc.) 575.6; (found) 576.5 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:16][CH2:17][CH3:18])=[C:5]([CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=1[O:11][CH3:12])C=O.CC1C=CC(S(O)(=O)=O)=CC=1.CO[CH:32]([O:35][CH3:36])[O:33][CH3:34].[OH-].[K+]>CO>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[C:4]([CH2:16][CH2:17][CH3:18])[C:5]([CH:32]([O:33][CH3:34])[O:35][CH3:36])=[CH:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(OC)OC
Reactant: CCCc1c(C=O)cc([N+](=O)[O-])c(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(OC)OC)cc([N+](=O)[O-])c(OC)c1OC

Procedure:
A solution of the aldehyde from step (d) (14 g) tosic acid (0.2 g) and trimethylorthoformate (6.7 ml) in dry methanol (100 ml) was heated under reflux for 30 mins. A solution of potassium hydroxide in methanol (5 ml) was added to the reaction mixture and the solution evaporated to dryness. The residue was dissolved in ether, washed with water, dried, filtered and evaporated to leave a solid which crystallised from pentane as pale yellow prisms (11.6 g); mp 52.1°-54.0°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(O)ccn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (5.0 g, 32.3 mmol) in DMF (50 mL) at 0° C. was added NaH (2.6 g, 64.0 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, benzyl bromide (6.03 g, 35.2 mmol) was added and the reaction was stirred at 55° C. for 17 h. The mixture was cooled to room temperature, poured into ice water, and filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was washed with EtOH to give 1-benzyl-4-hydroxy-3-nitro-1H-pyridine-2-one (3.30 g, 42% yield). 1H-NMR (DMSO): δ 7.90 (d, 1H, J=7.6 Hz), 7.27-7.38 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.08 (s, 2H). MS: calculated for C12H10N2O4+H 247.1; found: 247.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[OH-].[NH4+].S(S([O-])=O)([O-])=[O:16].[Na+].[Na+]>O>[NH2:10][C:4]1[C:5]([C:8]([NH2:9])=[O:16])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#Cc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(Cl)cc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274 mL, 10.9 mmol) in water (22 mL) was added 28% aqueous ammonium hydroxide (3.94 mL, 28.3 mmol), and the reaction was stirred at RT for 20 minutes. Sodium hydrosulfite (2.68 mL, 32.7 mmol) was added, and the reaction mixture was stirred at RT for 70 minutes. The yellow precipitate was collected by vacuum filtration to provide the title compound (1.097 g, 6.39 mmol) as yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (br. s, 1H), δ7.73 (s, 1H), δ7.39 (br. s, 1H), δ7.23 (s, 1H), δ7.06 (br. s, 2H). LC/MS (ESI+) m/z=172 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: COc1ccc2c(c1)CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 51 %

Procedure:
141 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 104 mg of 5-methoxyisoindoline, 121 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 105 mg of the target compound.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH2:7])=[O:5])[CH2:3][CH2:2]1.[C:8](=S)=[S:9]>CN(C)C=O>[SH:9][C:8]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:6][N:7]=1
Reactant: S=C=S
Reactant: NNC(=O)C1CC1
Solvent: CN(C)C=O
Product: Sc1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 17.9 g (0.179 mole) cyclopropane carboxylic acid hydrazide (the product of Example 6) in about 75 ml dimethylformamide, 68.0 g (0.894 mole) carbon disulfide was added (and all solids dissolved). The solution turned orange and then green. The reaction mixture was stirred about 1 hour at room temperature, refluxed about 3 hours, and stirred overnight at room temperature. The mixture was added to an ice-water bath to give an oil. The mixture was extracted with methylene chloride. The methylene chloride fraction was dried over magnesium sulfate and stripped. Chromatography on silica gel, eluting with methylene chloride, gave the above-identified product as a solid, melting point 76°-78° C.
Reaction SMILES: C[Si](C)(C)[N:3]1[N:7]=[CH:6][CH:5]=[N:4]1.[N+](C1C=CC(S(O[CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)(=O)=O)=CC=1)([O-])=O>CN(C=O)C>[N:4]1([CH:27]2[CH2:28][CH2:23][CH2:24][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH:5]=[CH:6][N:7]=[N:3]1
Reactant: C[Si](C)(C)n1nccn1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ccnn2)C1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A 1000-mL 4-necked round-bottomed flask was charged with a solution of 2H-1,2,3-triazole (30 g, 434.78 mmol, 1.00 equiv) in benzene (500 mL). To this solution was added chlorotrimethylsilane (49.3 g, 456.48 mmol, 1.05 equiv) drop wise 0° C. followed by addition of triethylamine (48.3 g, 478.22 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140-150° C. affording 2-(trimethylsilyl)-2H-1,2,3-triazole as colorless oil (11 g, 18%). To a solution of 2-(trimethylsilyl)-2H-1,2,3-triazole (6.2 g, 43.97 mmol, 2.74 equiv) in DMF (100 mL) was added tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate (6.2 g, 16.06 mmol, 1.00 equiv). The resulting solution was refluxed for 3 hours. Upon completion, the mixture was cooled down to room temperature and concentrated on a rotary evaporator affording tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as brown solid (2.3 g).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[NH2:21])C1C=CC=CC=1.ClCCl>[Pd].CO>[NH2:21][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[OH:8])=[N:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2
Reactant: COc1ccc2ncc(N)c(OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(N)c(O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
10% Palladium on activated carbon (76 mg, 0.07 mmol, 0.1 eq) is added at room temperature to a stirred solution of 4-benzyloxy-6-methoxy-[1,5]naphthyridin-3-ylamine (200 mg, 0.71 mmol, 1.0 eq) in methanol (20 mL). The resulting mixture is stirred under hydrogen flow (3 bars) at room temperature for 16 hours. The catalyst is then removed by filtration and the solution is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1 to 10:1, v/v) to afford 3-amino-6-methoxy-[1,5]naphthyridin-4-ol as a yellow solid (39 mg, 29% yield).
Reaction SMILES: Cl.[F:2][C:3]([F:10])([F:9])[C:4]([CH3:8])([NH2:7])[CH2:5][NH2:6].[F:11][C:12]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:13]=1[CH2:14][O:15][C:16]1[C:17]2[N:18]([C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:7][C:4]([CH3:8])([C:3]([F:10])([F:9])[F:2])[CH2:5][NH:6][C:27]([C:23]1[N:18]2[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([O:15][CH2:14][C:13]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:12]=3[F:11])[C:17]2=[N:25][C:24]=1[CH3:26])=[O:28]
Reactant: CC(N)(CN)C(F)(F)F
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(N)C(F)(F)F)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
118 mg (0.66 mmol) of rac-3,3,3-trifluoro-2-methylpropane-1,2-diamine hydrochloride Example 246A were added to 200 mg (0.60 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 203 mg (0.63 mmol) of TBTU and 0.27 ml (2.41 mmol) of 4-methylmorpholine in DMF (2.1 ml), and the reaction mixture was stirred at RT overnight. 50 mg (0.28 mmol) of rac-3,3,3-trifluoro-2-methylpropane-1,2-diamine hydrochloride Example 246A were added to the reaction mixture, and stirring was continued at RT overnight. The mixture was diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. This gave 219 mg (79% of theory, purity 99%) of the target compound.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Product: CCOc1nc(C)c(CC)cc1NC(=O)N1CCN(c2ccccc2OC)CC1
Yield: 82 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.