Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].[Br:37]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:37])[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])=[CH:19][CH:18]=1
Reactant: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(OCCOC)nc32)cc1)OCC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1ccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of diethyl 4-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzylphosphonate (1 equiv.) in acetic acid (0.20 M) was added sodium acetate (15 equiv.) and bromine (13 equiv.). The reaction mixture was then allowed to stir at room temperature for 18 h. At this point the reaction was quenched by the addition of sodium thiosulfate. The mixture was then diluted with water and DCM. This mixture was transferred to a separatory funnel and washed with DCM three times. The combined organic layers were then dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (14%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:20]([CH2:21][N:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][NH:18][C:4]=2[N:5]=[C:6]([NH:8]C(=O)CCCCCCC)[N:7]=1.Cl[CH2:38][C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:20]([CH2:21][N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:19][N:18]([CH2:38][C:39]3[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CCCCCCCC(=O)Nc1nc(Cl)c2c(CN(Cc3ccccc3)Cc3ccccc3)c[nH]c2n1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2cc(CN(Cc3ccccc3)Cc3ccccc3)c3c(Cl)nc(N)nc32)c1C
Temperature: 45 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A suspension of octanoic acid {4-chloro-5-[(dibenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide (150 mg, 0.30 mmol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (56 mg, 0.30 mmol) and K2CO3 (84 mg, 0.60 mmol) in dry DMF (1 mL) was heated to 45° C. overnight. After work-up (EtOAc) and evaporation, the residue was taken up in methanolic 4N HCl (1 mL), stirred at room temperature for 1 h, and neutralized to pH 7 with 2N NaOH. Extraction with EtOAc (10 mL×3), evaporation and purification by preparative TLC (MeOH/CH2Cl2 10:1) gave the title compound (70.5 mg, 45%). HPLC Rt: 5.362 min. 1H-NMR (DMSO-d6): δ 8.05 (s, 1H), 7.30–7.22 (m, 10H), 6.99(s, 1H), 6.57 (s, 2H), 5.27 (s 2H), 3.70 (s, 2H), 3.65 (s, 3H), 3.54 (s, 4H), 2.17 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31])C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[C:13]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[N:12]([CH3:21])[C:11](=[O:22])[C:10]=1[C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[CH3:31]
Reactant: CON1CCC2(CC1)C(OCc1ccccc1)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2C
Reaction time: 22 h

Procedure:
To a solution of 4-benzyloxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (22.6 g, 53.7 mmol) in methanol (226 ml) and water (22.6 ml) in a Parr shaker type hydrogenator was added 5% Pd/C (22.6 g). After hydrogenation under 4 bars H2 at 36° C. for 22 hours, the reaction mixture was filtered and concentrated. The residue was diluted with ethyl acetate and extracted with saturated aqueous sodium carbonate under ice cooling. The organic layer was discarded, the aqueous alkaline phase acidified with cooling to pH 5-6 with an aqueous HCl solution and thoroughly extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Yield: 13.0 g of 4-hydroxy-8-methoxy-1-methyl-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a solid, mp 239-241° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([O:30]C)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:12](=[O:34])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)Oc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoate (0.37 g, 0.7 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide solution (2 ml). The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were crystallized from ethyl acetate-diisopropyl ether to give 2-[(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]-2-methylpropanoic acid (0.32 g, 91.4%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[C:9]([C:16]([O:18]CC4C=CC=CC=4)=[O:17])[C:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]4[C:26](=[O:30])[NH:27][C:28](=[O:29])[C:7]=4[C:6]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2[nH]c3cc(C(=O)O)c4c(c3c2c1)C(=O)NC4=O
Reaction time: 2 h

Procedure:
A solution of benzyl 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylate (2.00 g), prepared as in example 3, in DMF/MeOH (4:1) (50 mL) containing 5% Pd-C (0.50 g) was hydrogenated at 60 psi for 2 h (Parr apparatus). The solution was filtered through a plug of Celite, which was washed 6 times with neat DMF followed by MeOH (several cycles). The combined filtrate and washings were concentrated to dryness in vacuo and the residue was slurried with diethyl ether to give the 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid (5) as a greenish solid. The reaction was repeated 5 times on this scale to and the products were combined to give 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid, (8.1 g, 84%). A portion of the product was purified by adsorption onto silica, followed by chromatography on silica, eluting with EtOAc. The product was triturated with diethyl ether to give 9-methoxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazole-4-carboxylic acid as an orange solid; mp>300° C. 1H NMR δ [(CD3)2SO] 12.15 (s, 1H), 8.42 (d, J=2.5 Hz, 1H), 7.97 (s, 1H), 7.57 (d, J=8.8 Hz, 1H0, 7.25 (dd, J=8.8, 2.5 Hz, 1H), 3.82 (s, 3H), 3.40 (br, 2H). Found: C, 58.69; H, 3.55; N, 8.40. C16H10N2O5,H2O requires C, 58.54; H, 3.68; N, 8.53.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:24][C:25]([O:28][C:29](ON=C(C1C=CC=CC=1)C#N)=[O:30])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([O:28][C:29](=[O:30])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCNC1CCCc2cccnc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.4 %

Procedure:
To a solution of N-(5,6,7,8-tetrahydro-quinolin-8yl)-butane-1,4-diamine (6.77 g, 30.9 mmol) in tetrahydrofuran (155 ml) was added slowly triethylamine (4.30 ml, 30.9 mmol) and Boc-ON (7.60 g, 30.9 mmol). The mixture was stirred for 72 hours at room temperature under a N2 atmosphere. The mixture was concentrated and purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v). A second purification by column chromatography on silica gel (ethyl acetate) afforded the product as a brown oil (8.03 g, 80%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.60 (s, 4H), 1.78 (m, 2H), 1.99 (m, 2H), 2.78 (m, 5H), 3.15 (m, 2H), 3.77 (t, 1H), 4.87 (s, 1H), 7.07 (dd, 1H, J=7.45, 4.82 Hz), 7.83 (d, 1H, J=7.89 Hz), 8.38 (d, 1H, J=4.38 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]([Cl:20])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
4-Chlorobenzylamine (7.3 mL, 60 mmol) was added dropwise to a stirred, cooled (˜0° C.), solution of 2,6-dichloro-3-nitropyridine (10.1 g, 52.2 mmol) and K2CO3 (7.93 g, 57.4 mmol) in MeCN (60 mL). After stirring for 5 hours at ambient temperature, the mixture was concentrated in vacuo and then partitioned between EtOAc and water. The EtOAc layer was then washed successively with aqueous potassium hydrogen sulfate solution, brine and then dried (MgSO4). The solution was evaporated in vacuo to give a yellow solid which was recrystallised from heptane/EtOAc (1:2) to give (4-chloro-benzyl)-(6-chloro-3-nitro-pyridin-2-yl)-amine as a yellow solid (7.67 g). The mother liquor was evaporated and the residue recrystallised from EtOH to give a second crop of product (3.39 g). MS: [M+H]+=298
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:26]([O:28]C(C)(C)C)=[O:27])[N:9]([CH2:14][C:15]3[CH:19]=[C:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[O:17][N:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:26]([OH:28])=[O:27])[N:9]([CH2:14][C:15]3[CH:19]=[C:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[O:17][N:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1cc(C(=O)OC(C)(C)C)n2Cc1cc(-c2ccc(Cl)s2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester were dissolved in 100 ml trifluoro-acetic acid and stirred for 1 h at RT. Then 100 ml toluene was added and the solvents were removed under reduced pressure. This procedure was repeated three times, then the residue was dried in vacuo.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCI
Reactant: c1ccc2c(c1)CCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCN1CCC2(CCc3ccccc32)CC1
Yield: 52.6 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was synthesised using spiro[indane-1,4'-piperidine] (0.4 g, 2.2 mmol), DMF (15 ml), potassium carbonate (0.33 g, 2.4 mmol) and iodohexane (0.62 g, 2.9 mmol). The crude residue was chromatographed in 1:1 petrol:ether to give 1'-hexylspiro[indane-1,4'-piperidine] (314 mg, 52%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:18])=[CH:5][C:6](=[O:17])[C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[CH3:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[C:6]([O:17][CH2:19][CH2:20][CH3:21])[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: CCCBr
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(C)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(C)nc(C)c1C(=O)Nc1ccccc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 75.3 %

Procedure:
A mixture of 2.42 (10 m mol) of 1,4-dihydro-2,6-dimethyl-4-oxo-N-phenyl-3-pyridinecarboxamide, 1.84 g (15 m mol) of n-propyl bromide, 1.52 g (11 m mol) of potassium carbonate and 40 ml of N,N-dimethylformamide was stirred for 7 hours at 90° C. (bath temperature). About 100 ml of water was added to the reaction mixture. The mixture was cooled to room temperature to precipitate crystals. The crystals were filtered off, washed and dried under reduced pressure to obtain 2.14 g of 2,6-dimethyl-N-phenyl-4-propoxy-3-pyridinecarboxamide
Reaction SMILES: [C:1]([NH:3][C:4]([NH:27][CH3:28])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]>[Pd]>[C:1]([NH:3][C:4]([NH:27][CH3:28])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:2]
Reactant: CNC(=NCCSCc1ncccc1OCCOCc1ccccc1)NC#N
Agent: [Pd]
Product: CNC(=NCCSCc1ncccc1OCCO)NC#N

Procedure:
N-Cyano-N'-methyl-N"-[2-((3-(2-benzyloxyethoxy)-2-pyridyl)methylthio)ethyl]guanidine which may be hydrogenolysed using palladium on charcoal catalyst to give N-cyano-N'-methyl-N"-[2-((3-(2-hydroxyethoxy)-2-pyridyl)methylthio)ethyl]guanidine
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].Cl.O[C@@H](CC(=O)[O-])C[N+](C)(C)C.[Cl-]>O>[CH3:1][N+:2]([CH2:5][C@H:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:3])[CH3:4]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: C[N+](C)(C)CC(O)CC(=O)O
Agent: C[N+](C)(C)C[C@@H](O)CC(=O)[O-]
Agent: Cl
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Yield: 75 %

Procedure:
The procedure of Example 8 was followed except that the concentration of DL-carnitine chloride for the F-2 stage was 50 g/l, which consisted of 8 parts of L-carnitine chloride and 2 parts of D-carnitine chloride. L-carnitine inner salt was isolated as before from 50 ml of the fermentation mixture (F-2 stage, 69 hours) [1.216 g (75% yield, [α]D25 -30.4°, c=2.8, H2O].
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[CH2:13][CH2:12]2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[CH2:13][CH2:12]2)[CH2:6]1
Reactant: N#Cc1ccccc1N1CCC(N2CCCC(CN=[N+]=[N-])C2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccccc1N1CCC(N2CCCC(CN)C2)CC1

Procedure:
The title compound was prepared from 24 (560 mg, 1.73 mmol) and triphenylphosphine (900 mg, 3.4 mmol) using the procedure described for 13.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][C:5]([C:12](OC)=[O:13])([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[CH3:11][O:10][C:8]([C:5]1([CH:12]=[O:13])[CH2:6][CH2:7][C:2]([CH3:16])([CH3:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: COC(=O)C1(C(=O)OC)CCC(C)(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: COC(=O)C1(C=O)CCC(C)(C)CC1
Reaction time: 2.5 h

Procedure:
To a solution of dimethyl 4,4-dimethyl-cyclohexane-1,1-dicarboxylate (5.23 g, 22.9 mmol) in diethyl ether (250 mL) at −78° C. under a nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 30.6 mL, 45.9 mmol) dropwise. After 2.5 h, the reaction mixture was quenched with a mixture of methanol (75 mL) and water (75 mL). The mixture was filtered through Celite@ and the aqueous phase was extracted with diethyl ether (100 mL×5), was dried (MgSO4) and was evaporated in vacuo to yield the title compound which was used without further purification. MH+199.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[C:8]([C:19](OCC)=[O:20])=[CH:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]=12>C1COCC1>[N:7]1[C:8]([CH2:19][OH:20])=[CH:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]=12
Reactant: CCOC(=O)c1cn2c(n1)sc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cn2c(n1)sc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of LiAlH4 (2.0 g, excess) in dry THF, ethyl imidazo[2,1-b]-benzthiazole-2-carboxylate (4.9 g, 20 mmol) was slowly added in THF (100 ml) at 0° C. After the addition, the reaction mixture was stirred at room temperature for 1 h and quenched with saturated NH4Cl/NH4OH. The separated solid was diluted with Chloroform/MeOH (3:1) and filtered through a pad of celite. The organic layer was washed once with saturated NaCl and dried over anhydrous MgSO4. It was filtered and concentrated. The brown solid obtained was taken to next step with out purification. Yield: 3.8 g, 93%; M+H 205; mp 131° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:18])=[CH:14][CH:15]=3)[C:10]([CH3:25])=[C:9]2[CH3:26])=[CH:5][CH:4]=1.C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH:20]4[CH2:24][CH2:23][N:22]([CH3:31])[CH2:21]4)=[O:18])=[CH:14][CH:15]=3)[C:10]([CH3:25])=[C:9]2[CH3:26])=[CH:27][CH:28]=1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCNC3)cc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NC3CCN(C)C3)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 317 mg portion of 1-(4-fluorobenzyl)-2,3-dimethyl-N-pyrrolidin-3-yl-1H-indole-5-carboxamide hydrochloride was suspended in 8 ml of dichloromethane, 0.11 ml of triethylamine and 0.13 ml of formaldehyde (a 37% aqueous solution) were added, and then 836 mg of sodium triacetoxy borohydride was added under ice-cooling, followed by stirring at room temperature for 1.5 hours. A 1 M sodium hydroxide aqueous solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:1:0.1 to 50:1:0.1 to 30:1:0.1 to 20:1:0.1) to obtain 279 mg of 1-(4-fluorobenzyl)-2,3-dimethyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-5-carboxamide as a colorless solid. This product was suspended in 2 ml of ethanol, and 0.27 ml of 4 M hydrogen chloride-ethyl acetate was added, followed by stirring at room temperature for 2 hours. After evaporation of the solvent under a reduced pressure, the residue was dissolved in 2 ml of acetone, followed by stirring at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with acetone to obtain 261 mg of 1-(4-fluorobenzyl)-2,3-dimethyl-N-(1-methylpyrrolidin-3-yl)-1H-indole-5-carboxamide hydrochloride as a pale pink solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[O-:13][C:14]#[N:15].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]([NH2:15])=[O:13])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
4-aminophenol (45 g, 0.4123 mol) was charged in water and acetic acid mixture (9:1) (450 vol) to obtain a clear solution. To this clear solution was added drop wise previously prepared solution of sodium cyanate (29.48 g, 0.45358 mol) in water over a period of 1 hour. The reaction mass obtained was stirred for 6 hours at ambient temperature and filtered to obtain solid. The solid was washed with water and vacuum dried to obtain the desired product, i.e., 1-(4-hydroxyphenyl)urea (48 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1.CC(C)=O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16][C:18]1([CH3:23])[CH3:19]
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)C
Yield: 13.9 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (400 mg, 1.72 mmol), p-toluenesulfonic acid monohydrate (150 mg) and acetone (40 mL) in toluene (40 mL) was heated to reflux overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel (MeOH: dichloromethane=1:9) to afford the title compound (30 mg, yield 6%) as an orange solid:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:12](=[O:21])[N:13]([CH3:20])[N:14]=[C:15]([CH3:19])[C:16]=2[O:17][CH3:18])[CH:3]=1.C([O-])(O)=O.[Na+].C(Cl)[Cl:28]>>[CH3:18][O:17][C:16]1[C:15]([CH3:19])=[N:14][N:13]([CH3:20])[C:12](=[O:21])[C:11]=1[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([Br:1])=[C:3]1[Cl:28]
Reactant: COc1c(C)nn(C)c(=O)c1-n1cc(Br)c2ccccc21
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1c(C)nn(C)c(=O)c1-n1c(Cl)c(Br)c2ccccc21
Reaction time: 0.08 h
Yield: 87 %

Procedure:
A solution of SO2Cl2 (47 μl, 0.583 mmol) in DCM (2 mL) is added dropwise to a solution of 4-(3-bromoindol-1-yl)-5-methoxy-2,6-dimethyl-pyridazin-3-one (203 mg, 0.583 mmol) in DCM (6 mL) at 0° C. The solution went pale yellow. After stirring for 5 min the cooling bath is removed and the resulting reaction mixture stirred at ambient temperature for 2 h. The reaction mixture is shaken well with a solution of NaHCO3. The layers are separated and the aqueous layer extracted with DCM (3×20 mL). The combined DCM layers were filtered through MgSO4 and concentrated in vacuo. The resulting solid was purified by flash chromatography (combiflash, 0 to 10% DCM/EtOAc) to yield the desired product 5-methoxy-2,6-dimethyl-4-(2-chloro-3-bromoindol-1-yl)pyridazin-3-one (194 mg, 0.507 mmol, 87% Yield).