Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:44][CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1cccnc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2cccnc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-picolylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.Cl.C(N(C(C)C)CC)(C)C>C(#N)C.[Cl-].[Na+].O>[Cl:26][C:4]1[N:3]=[C:2]([NH:27][CH2:28][CH2:29][C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: NCCc1cccc(O)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Oc1cccc(CCNc2cc(-c3c[nH]c4ncccc34)cc(Cl)n2)c1
Temperature: 60 °C

Procedure:
A mixture of Example 7a (75.0 mg, 0.186 mmol), 3-(2-aminoethyl)phenol.HCl (0.250 g, 1.44 mmol), and diisopropylethylamine (0.52 mL, 2.97 mmol) in acetonitrile (0.6 mL) was heated in a Biotage microwave reactor at 160° C. for 30 minutes. The reaction mixture was treated with 20% brine and extracted with EtOAc (2×). The combined organic layers were washed with 20% brine, dried over MgSO4, filtered, and concentrated. The crude was dissolved in dioxane (1.3 mL) and treated with 20% NaOH (0.12 mL). The mixture was heated at 60° C. for 1 hour and concentrated. The residue was treated with water, sonicated, filtered, washed with water, and dried. The crude material was purified on a 4 g column using the ISCO Companion flash system eluting with CH2Cl2/MeOH (97:3 to 90:10) to give 5.5 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 2.77 (t, J=7.32 Hz, 2H), 3.46 (t, J=6.87 Hz, 2H), 6.61 (d, J=7.93 Hz, 1H), 6.65-6.74 (m, 2H), 6.87 (s, 1H), 6.89-6.98 (m, 2H), 7.09 (t, J=7.78 Hz, 1H), 7.21 (dd, J=7.93, 4.88 Hz, 1H), 8.14 (d, J=2.75 Hz, 1H), 8.25-8.35 (m, 2H), 9.27 (s, 1H), 12.16 (s, 1H). MS (DCI+) m/z 365.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-Indole amine (0.6 g, 4.54 mmol) in anhydrous dichloromethane (15 mL), triethylamine (1.3 mL, 9.0 mmol) and pivaloyl chloride (0.45 mL, 5.4 mmol) were added and stirred at room temperature for 2 h. The reaction mixture was diluted with water; the organic layer was separated and concentrated in vacuo. The resultant residue was purified by flash column chromatography to give N-(1H-indol-5-yl)pivalamide (0.88 g, 89%); MS: 217.0 (M+1).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.Br.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:22][CH:21]=1>C1COCC1.C(N(CC)CC)C>[ClH:10].[OH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:24][CH:25]=1
Reactant: NCCCCc1ccc(O)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Br
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cl
Product: N=C(NCCCCc1ccc(O)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Reaction time: 3 h
Yield: 84.4 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.4 g, 1.03 mmol) was added to a suspension of 4-(4-hydroxyphenyl)butylamine hydrobromide (4) (0.8 g, 32 mmol) in a mixture of THF (35 mL) and triethylamine (3 mL). The reaction mixture was stirred in the boiling solvent for 3 h, then the supernatant was separated and the solvent was removed under reduced pressure. The oily residue was washed with water (2×30 mL), ether (3×30 mL) and then 10% HCl (40 mL) was added. The mixture was vigorously stirred for 10 min then the yellow solid was filtered off, dried and recrystallized twice from ethanol to give 5 (0.18 g, 41%) as yellow solid. Purity is 98% by HPLC, retention time is 9.77 min. 1H NMR (300 MHz, DMSO-d6) δ 1.56 (br s, 4H), 2.48 (br s, 2H), 3.35 (m, 2H), 6.65 (d, 2), 6.95 (d, 2H), 7.50 (br s, 2H), 8.75 (br s, 1H), 9.05 (br s, 1H), 9.33 (br s, 2H), 10.55 (s, 1H). 13C NMR (75 MHz, CD3OD) 28.7, 29.8, 35.4, 42.4, 111.2, 116.1, 122.0, 130.0, 134.0, 155.0, 156.1, 156.8, 157.5, 167.0. APCI MS m/z=378 [C16H20ClN7O2+H]+.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24](Cl)=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(Cl)Cl.[OH:30][CH:31]([CH2:36][CH3:37])[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>CCOCC>[CH2:2]([NH:18][C:19]1[CH:20]=[C:21]([C:24]([O:30][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH2:36][CH3:37])=[O:25])[S:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(=O)Cl)c1
Reactant: CCC(O)C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(CC)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10 g. of 4-hexadecylamino-2-thiophenecarbonyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several protions of ether. The ether solution is washed with water, dried and evaporated to yield 1-(methoxycarbonyl)propyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][S:11][C:12](S(C)=O)=[CH:13][N+:14]([O-:16])=[O:15].C[O-].[Na+]>CO>[CH3:10][S:11][C:12]1[NH:2][CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CCCCC(=O)CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 48.5 %

Procedure:
1-Amino-2-hexanone hydrochloride (5.8 g) was dissolved in methanol (100 ml) and mixed with a solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (6.8 g) in warm methanol (100 ml). A solution of sodium methoxide in methanol (from 1.7 g sodium) was added dropwise, with stirring, over 2 hours at 60°, and the mixture was evaporated to dryness. The residue was triturated with water, and the solid was filtered off and dried, to give 2-methylthio-3-nitro-4-n-butylpyrrole (3.9 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Br:18][CH2:19][C:20](Br)=[O:21]>C1COCC1.C(=O)=O.CC(C)=O>[Br:18][CH2:19][C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:21]
Reactant: O=C(Br)CBr
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(CBr)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (4R)-4-phenyl-1,3-oxazolidin-2-one (100 g, 613 mmol) in THF (2 L) under a nitrogen atmosphere was cooled to −78° C. in dry ice-acetone bath. To the stirred solution was added n-BuLi (337 mL, 2 M solution in cyclohexane, 675 mmol) dropwise over a period of 30 min, followed by the addition of 2-bromoacetyl bromide (123.7 g, 613 mmol) over 15 min. The resulting solution was stirred at 25° C. for 2 h. The reaction was quenched with aqueous NH4Cl (500 mL), and the mixture was extracted three times with EtOAc (3×1 L). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a brown solid. The crude product was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].I[CH3:13].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH3:13])[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(C)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a mixture of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (7.1 g, 46.05 mmol), iodomethane (5.73 mL, 92.1 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (NaH) (2.39 g, 59.9 mmol, 60% in mineral oil) in one portion, the mixture was stirred at 0° C. for 1 h then the mixture was poured into ice-water (300 mL), extracted with EtOAc, the organic phase was washed with diluted HCl aqueous solution, water and saturated NaCl aqueous solution respectively; the EtOAc layer was then dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified with column to give a colorless oil, the desired title compound (3.25 g); 1H NMR (200 MHz, CDCl3): δ (ppm)=6.5-6.4 (m, 2H), 4.24 (q, 2H, J=7.1 Hz), 3.52 (s, 3H), 2.49 (s, 3H), 1.33 (t, 3H, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[N:28]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:22]=[CH:23][C:24]4[NH:25][C:38]([C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:41][CH:40]=5)=[N:1][C:4]=4[CH:5]=3)=[O:21])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 212 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholin-4-ylbenzoyl)aniline and 4-morpholinylbenzaldehyde. [M+H]+ calcd for C28H29N5O3: 484.23; found: 483.94.
Reaction SMILES: Cl.[Cl:2]C1C=C(C(C2(O)CCN(C)CC2)CN2CCNCC2)C=CC=1Cl.[CH2:26]([NH:33][C:34](=O)[CH:35]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:36]1([OH:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:2].[CH2:26]([NH:33][CH2:34][CH:35]([C:36]1([OH:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccccc1)C(c1ccc(Cl)c(Cl)c1)C1(O)CCCCC1
Reactant: CN1CCC(O)(C(CN2CCNCC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: OC1(C(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 4-[1-(3,4-dichlorophenyl)-2-piperazin-1-ylethyl]-1-methylpiperidin-4-ol hydrochloride was prepared from N-benzyl-2-(3,4-dichlorophenyl)-2-(1-hydroxycyclohexyl)acetamide. HRMS: calcd for C21H25Cl2NO HCl, 413.1080; found (ESI_FT), 378.13864.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12]1=[O:19].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12]1=[O:19]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)ccc2F)C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)c([N+](=O)[O-])cc2F)C1=O
Reaction time: 8 h

Procedure:
26.3 g of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide are introduced in portions, at 5°, into 230 ml of 96% sulphuric acid. There is then added dropwise to this mixture, while stirring vigorously at the same temperature, 5 ml of 100% nitric acid. The whole is further stirred overnight at room temperature and then poured onto ice. The product which precipitates is filtered with suction, washed with water, dried and recrystallised from acetonitrile. 28 g of N-(2-fluoro-5-carboxy-4-nitrophenyl)-2,3-dimethylmaleic acid imide which has a melting point of 264°-265° is thus obtained.
Reaction SMILES: Cl.[C:2](=N)([O:4]C)C.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9].O[CH:22]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>CO>[CH3:22][O:20][C:17]([O:4][CH3:2])([C:14]1[CH:13]=[CH:12][C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=1)[CH2:18][CH3:19]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Product: CCC(OC)(OC)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 11.33 g. (0.10 mole) of methyl acetimidate hydrochloride, prepared by known procedures, in a 100 ml. 3-necked, round-bottomed flask there was added a solution of 9.71 g. (actual 9.42 g.; 49.6 mmole) of crude p-isobutylpropiophenone, prepared as described in Part A above, in 23 ml. of absolute methanol. The resulting solution was stirred for 12 hours at room temperature to insure complete reaction. Gas liquid chromatographic analysis (Glc analysis) of an aliquot of the reaction mixture indicated greater than 99% ketal formation. The resulting mixture was filtered to remove the precipitated ammonium chloride and concentrated under vacuum. Hexane (50 ml.) was added to the residue and the resulting solution was again filtered to remove any acetamide which might be present. Removal of the hexane solvent under vacuum gave p-isobutylpropiophenone dimethyl ketal as a pale yellow oil which was used without further purification. The NMR was in accord.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]3)[O:9][C:4]=2[CH:3]=1.[Br:28]N1C(=O)CCC1=O.C(C(N=NC(C)(C)C#N)(C)C)#N>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:13][CH2:14]3)[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OC1(CCN(C(=O)C(F)(F)F)CC1)c1ccc(C#N)n1-2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc2n1-c1ccc(CBr)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Temperature: 80 °C
Yield: 17.6 %

Procedure:
7′-Methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (250 mg, 0.666 mmol), 1-bromopyrrolidine-2,5-dione (119 mg, 0.666 mmol) and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (10.9 mg, 0.0666 mmol) were combined in carbon tetrachloride and the mixture was heated at 80° C. for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give 7′-(bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (53.2 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2cccnc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1cccnc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-pyridin-3-yl-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 days under reflux conditions to give the title compound as colorless oil. MS: m/e=446.0 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([Cl:18])[C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH:19]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:17])[C:10]=3[Cl:18])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)ccc2c1=O
Temperature: 25 °C

Procedure:
A quantity of 1.93 g of ethyl-1-cyclopropyl-1,4-dihydro-7-fluoro-8-chloro-4-oxo-quinoline-3-carboxylate is dissolved in 30 ml of a mixture of acetic acid, water and sulfuric acid (8/6/1). the mixture is refluxed for 3 hours and cooled to room temperature. The desired compound is collected by filtration and air dried.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[O:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=2)[CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:41]3[CH:40]=[N:39][C:38]([N:35]5[CH2:34][CH2:33][O:32][CH2:37][CH2:36]5)=[CH:43][CH:42]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(N2CCOCC2)nc1)N1CCN(C2CCC2)CC1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 2-morpholino-5-pyridineboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (29%).
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH:12]1([CH2:15][NH:16][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: NCC1CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl N-(2-oxoethyl)carbamate (1 g) was dissolved in dry methanol (40 ml) and treated with cyclopropane methylamine (0.709 ml) and 4A° molecular sieves (1 g) and the resultant mixture stirred at room temperature for 5 h. Sodium borohydride (0.38 g) was added and the reaction stirred for a further 18 h at room temperature. Sodium hydroxide (2N, 3 ml) was added, the mixture filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide solution (2N) and ethyl acetate. The separated organic layer was dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (1 g) as a colourless oil
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][OH:26]>CN(C)C=O.C(OCC)(=O)C>[OH:26][CH2:25][CH2:24][CH2:23][O:10][N:11]1[C:12](=[O:21])[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCCO
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Diisopropylethylamine (43 mL, 246 mmol) was added to a stirring solution of N-hydroxyphthalimide (20.6 g, 123 mmol) in dimethylformamide (95 mL). After 5 minutes, 3-bromopropanol (11.5 mL, 127 mmol) was added and the reaction mixture was heated to 80° C. for 18 h. The cooled solution was diluted with ethyl acetate (700 mL) and was washed with water (4×500 mL) and saturated brine (2×500 mL), dried over sodium sulfate and concentrated to an oil that solidified on standing to afford 2-(3-hydroxy-propoxy)-isoindole-1,3-dione (17.5 g, 65% yield) as a tan-colored solid: 1H NMR (400 MHz, CDCl3) δ 7.81 (m, 2H), 7.74 (m, 2H), 4.36 (t, 2H, J=5.6 Hz), 3.92 (t, 2H, J=5.9 Hz), 1.98 (quintet, 2H, J=5.9 Hz).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:14]=NC=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([N:21](CC)CC)C.[F:26][C:27](F)(F)[C:28]([O:30]C(=O)C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:21]=[CH:19][CH:14]=1)[C:28](=[O:30])[CH2:27][F:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccc(CNCCCSc2cccnc2)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CF)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 60.7 %

Procedure:
To a solution of 7.27 g (28.1 mmol) 4-[3-(N-benzylaminopropylthio)pyridine and 4.70 ml (33.7 mmol) of triethylamine in 150 ml of methylene chloride, 4.76 ml (33.7 mmol) of trifluoroacetic anhydride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/hexane=2:1 to 1:1) to obtain 6.04 g of 4-[3-(N-benzyl-N-fluoroacetylamino)-propylthio]pyridine (yield: 60.7% yellow oil).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:18]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCl
Reactant: Sc1ccccc1
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCSc1ccccc1

Procedure:
Using the general method of Example 37 Part D, N-(5-chloropentyl)-3-nitroquinolin-4-amine (10 g, 34 mmol) was reacted with benzenethiol (1.1 eq) to provide 12.6 g of 3-nitro-N-[5-(phenylthio)pentyl]quinolin-4-amine as a solid.