Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:19][CH2:18][C:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:7][C:8]=2[CH:13]=1)(=[O:16])=[O:15])([CH3:20])[CH3:21])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CO)ccc2n1CC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)COS(C)(=O)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-ol (Step H, 356 mg, 0.94 mmol) in dichloromethane (8 mL) were added triethylamine (157 μL, 1.13 mmol) and methanesulfonyl chloride (87 μL, 1.13 mmol) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (30 mL×3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude title compound (411 mg) as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nccn1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Temperature: 0 °C
Yield: 22 %

Procedure:
Ethyl 1-methylimidazole-2-carboxylate was carefully dissolved in 1000 mL of concentrated sulfuric acid cooled to 0° C. 90% nitric -acid (1 L) was slowly added maintaining a temperature of 0° C. The reaction was then refluxed with an efficient condenser (−20° C.) in a well ventilated hood for 50 min. The reaction was cooled with an ice bath, and quenched by pouring onto 10 L ice. The resulting blue solution was then extracted with 20 L DCM, the combined extracts dried (sodium sulfate) and concentrated in vacuo to yield a tan solid which was recrystallized from 22 L of 21:1 carbon tetrachloride/ethanol. The resulting white crystals are collected by vacuum filtration to provide pure Ethyl 1-methyl-4-nitroimidazole-2-carboxylate. (103 g, 22% yield). TLC (7:2 benzene/ethyl acetate v/v) Rf 0.5, 1H NMR (DMSO-d6) δ8.61 (s, 1H), 4.33 (q, 2H, J=6.4 Hz), 3.97 (s, 3H), 1.29 (t, 3H, J=6.0 Hz), 13C NMR (DMSO-d6) δ158.2, 145.4, 135.3, 127.4, 62.2, 37.3, 14.5; IR(KBr) 3139, 1719, 1541, 1498, 1381, 1310, 1260, 1122, 995, 860, 656.; FABMS m/e 200.066 (M+H200.067 calc. for C7H10N3O4).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl.[OH2:26].CO>CS(C)=O.C(Cl)(Cl)Cl>[OH2:7].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:26])[C:10]([OH:12])=[O:11])=[O:7])=[CH:23][CH:24]=1
Reactant: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.8 Grams of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid prepared in Reference Example 6 was suspended in 8 g of dimethyl sulfoxide, then 17 g of concentrated hydrochloric acid was added to the suspension, and the resulting mixture was stirred at a room temperature for 2 hours. Further, 80 ml of water was added to the reaction mixture and stirred at a room temperature for 1 hour. The crystals formed were collected by filtration, washed with water, and dried. The crude crystals thus obtained were suspended in a mixture of chloroform:methanol=50:1 and stirred, the crystals were collected by filtration, and dissolved in a saturated sodium bicarbonate aqueous solution. The insoluble materials were removed by filtration, the filtrate obtained was neutralized with 10%-hydrochloric acid. The crystals formed were collected by filtration, washed with water, dried to obtain 3.2 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid monohydrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[OH:31])=[CH:8][CH:7]=1.Br[CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[O:31][CH2:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:8][CH:7]=1
Reactant: BrCC1CCCC1
Reactant: COC(=O)COc1ccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)COc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from {4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-phenoxy}-acetic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (57%). MS (Turbo Spray): m/z=540.9 (M+H).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]([CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH2:27])=[NH:26])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:8][CH:7]=1.Cl.[C:32](=[NH:37])(OCC)[CH3:33].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:32]([N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N:5]([CH2:19]/[CH:20]=[CH:21]/[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:27])=[NH:26])[CH3:4])=[CH:7][CH:8]=2)[CH2:18][CH2:17]1)(=[NH:37])[CH3:33]
Reactant: CCOC(C)=N
Reactant: CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1COCCO1
Product: CC(=N)N1CCC(Oc2ccc(N(C)C/C=C/c3cccc(C(=N)N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 216.1 %

Procedure:
To a solution of 3-[3-[N-methyl-N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (368 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (290 mg) and triethylamine (0.65 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 10% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (288 mg, yield 72%) as a pale brown amorphous solid.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([CH3:14])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[OH-].[Na+:16]>C(Cl)(Cl)Cl.O.CCO>[CH3:14][C:8]1[C:7]([Cl:6])=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][S:2](=[O:4])(=[O:3])[O-:5].[Na+:16]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Cl)cccc1NS(=O)(=O)[O-]
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
Chlorosulfonic acid (516 μl, 7.77 mmol) in chloroform (5 ml) was added dropwise to a solution of 3-chloro-2-methylaniline (844 μl, 6.98 mmol) and TEA (7.8 ml, 56.54 mmol) in chloroform (20 ml) at 0° C. The mixture was stirred for 90 min, concentrated in vacuo and a solution of NaOH (848 mg, 21.2 mmol) in water (10 ml) was added and the mixture stirred for 30 min at room temperature. The reaction was concentrated in vacuo and azeotroped with toluene. The solid obtained was heated in EtOH (50 ml) at 60° C. for 15 min, concentrated in vacuo and EtOAc (50 ml) added. The resulting solid was collected by filtration and the filtrate allowed to stand at room temperature for 4 h. The crystals formed were filtered, washed with EtOAc, and the solids combined to give the title compound (1.44 g, 84%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]1O)([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH:1]([C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:3])[CH3:2]
Reactant: CC(C)C1Cc2ccccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C1=Cc2ccccc2C1

Procedure:
2-i-Propyl-1-indanol, non-purified, was dissolved in 300 ml of benzene to which was added 5 g of p-toluenesulfonic acid monohydrate and the resulting mixture was refluxed to allow dehydration reaction to occur. After the reaction was over, the reaction mixture was washed with saline, dried over magnesium sulfate, and concentrated in an evaporator. The reaction mixture was purified by column chromatography (silica gel, development solvent: n-hexane) to fractionate the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19](SC)SC)[CH:15]=[N:14]1.BrN1C(=O)CCC1=O.O.[NH2:33]/[C:34](/[C:39]#[N:40])=[C:35](\[NH2:38])/[C:36]#[N:37]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][CH:19]=[N:33][C:34]([C:39]#[N:40])=[C:35]([NH2:38])[C:36]#[N:37])[CH:15]=[N:14]1
Reactant: CSC(Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1)SC
Reactant: N#C/C(N)=C(/N)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: N#CC(N)=C(C#N)N=CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl]-4-[2,2-di(methylthio)ethyl]-2H-1,2,3-triazole was treated with N-bromosuccinimide in aqueous acetonitrile., After 10 minutes the mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-acetaldehyde. This was then treated with diaminomaleonitrile in a similar manner to Example 1, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl]-4-[2-(2-amino-1,2-dicyanoethenylimino)ethyl]-2H-1,2,3-triazole, which was cyclised in a similar manner to Example 1a, to give 2-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-[(4,5-dicyano-1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole (Compound 30).
Reaction SMILES: FC1C=C(C)C([C:9]2[C:18](=[O:19])[N:17](C)[C:16]3[N:15]=[C:14](NC)[N:13]=[CH:12][C:11]=3[N:10]=2)=CC=1NC(=O)C.Cl>CO>[N:15]1[C:16]2[NH:17][C:18](=[O:19])[CH:9]=[N:10][C:11]=2[CH:12]=[N:13][CH:14]=1
Reactant: CNc1ncc2nc(-c3cc(NC(C)=O)c(F)cc3C)c(=O)n(C)c2n1
Agent: Cl
Solvent: CO
Product: O=c1cnc2cncnc2[nH]1
Yield: 160.7 %

Procedure:
A solution of N-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropteridin-6-yl)phenyl)acetamide (1.5 g, 4.2 mmol) and conc. HCl (1 mL) in MeOH (20 mL) was heated at reflux overnight. The solvent was removed under reduced pressure. Water was added, and the mixture basified to pH=8. The resulting precipitate was collected by filtration and dried to give 6-(5-amino-4-fluoro-2-methylphenyl)-8-methyl-2-methylamino)pteridin-7(8H)-one (1.0 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 0.3 H), 8.62 (s, 0.7 H) □7.96 (m, 0.7 H) □7.85 (m, 0.3 H) □6.88 (d, J=12.4 Hz, 1 H), 6.78 (d, J=9.2 Hz, 1 H), 4.98 (s, 2 H), 3.56 (s, 2 H), 3.48 (s, 1 H) □2.91 (d, J=4 Hz, 3 H), 2.03 (s, 3 H). MS (ESI) m/z: 315.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][NH:21][C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:5][CH:4]=1.[C:22]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[C:37](O)=[O:38])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:37]([C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]4[NH:30][C:22](=[O:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:38])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:7][CH:8]=1
Reactant: CSc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc([C@@H]2Nc3ccccc3[C@H]3[C@@H]2CCN3C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a suspension of (3aS,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (1.10 g, 3.0 mmol) and (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (0.74 g, 3.0 mmol) in DMF (20 ml) were added under ice-cooling, triethylamine (0.91 g, 9.0 mmol), and then a solution of DEPC (0.49 g, 3.0 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hrs., the reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:1, v/v) to give N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl}carbonyl)cyclohexyl]benzamide (0.45 g, 29%) from the first eluted fraction.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH:8]1[N:12]2[C:13]3[CH2:24][C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:14]=3[NH:15][C:16](=[O:17])[C:11]2=[N:10][CH:9]=1.C([O-])(=O)C.[NH4+].C(OC(=O)C)(=O)C>>[S:1]1[C:5]([CH:6]=[C:24]2[C:13]3[N:12]4[CH:8]=[CH:9][N:10]=[C:11]4[C:16](=[O:17])[NH:15][C:14]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]2=3)=[CH:4][N:3]=[CH:2]1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: O=Cc1cncs1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cncs3)c2n2ccnc12
Yield: 54.5 %

Procedure:
The process is performed as in Example 92 but starting with 0.45 g of 5-thiazolecarboxaldehyde, 0.45 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 0.2 g of ammonium acetate and 4 ml of acetic anhydride. 0.35 g of 10-(5-thiazolylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a dark red solid melting above 260° C. (Analysis, % calculated C: 64.14, H: 3.17, N: 17.60, O: 5.03, S: 10.07, % found C: 64.2, N: 17.2, S: 9.7).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCCC1=O>CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:16])[C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCn1cc(C(=O)O)c(=O)c2c(F)c(F)c(N3CCOCC3)c(F)c21
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A mixture of 289 mg of 1-ethyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 300 mg of morpholine and 5.6 ml of 1-methyl-2-pyrrolidone was heated in a stoppered flask at 65° C. for one hour. Ether was added, the solid collected, dissolved in 200 ml of acetone, filtered and boiled down to about 50 ml. The solid was collected, giving 137 mg of the desired product, mp 281°-283° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nc(N2CCCCC2)c2cc[nH]c2n1
Temperature: 70 °C
Reaction time: 20 h
Yield: 97.9 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.531 mmol), piperidine (0.060 mL, 0.607 mmol) and triethylamine (0.200 mL, 1.43 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give 2-chloro-4-(piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (123 mg). MS 237.3 and 239.3 (M+H, Cl pattern)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[C:10]3[CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:21]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(Cl)cc2C=Cc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-chloro-dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:3]=1[C:4]([NH:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[O:5]>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH:12]=1)[C:4]([NH:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[O:5]
Reactant: N#CC1(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#CC1(NC(=O)c2cc(N)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.15 g of iron powder are suspended in 18 ml of 5% strength acetic acid, and a solution of 3.0 g of 2-chloro-N-(1-cyanocyclopropyl)-5-nitrobenzamide in a mixture of 25 ml of ethyl acetate and 22.6 ml of glacial acetic acid is added. During the addition, the internal temperature is kept below 45° C. The reaction mixture is stirred at room temperature for 14 hours and then filtered through Celite. The filtrate is diluted with water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated on a rotary evaporator under reduced pressure. The crude product is triturated with a mixture of three parts of cyclohexane and one part of ethyl acetate, and the solid is filtered off. This gives 2.0 g (71%) of 5-amino-2-chloro-N-(1-cyanocyclopropyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([F:18])[CH:12]=3)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]([OH:54])[CH2:50][CH2:51][CH:52]=[CH2:53].C([NH2+]C(C)C)(C)C.F[B-](F)(F)F.C(N(CC)CC)C.F[B-](F)(F)F.[H+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][O:54]4)=[CH:3][CH:4]=3)[NH:9][C:10]2=[O:19])=[CH:15][CH:14]=1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2ccc(F)cc12
Reactant: C=CCCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)[NH2+]C(C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(c2ccc(-c3cc4ccc(F)cc4c(=O)[nH]3)cc2)CCCO1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
3-(4-Bromo-phenyl)-7-fluoro-2H-isoquinolin-1-one (159 mg, 0.50 mmol), palladium(II)acetate (5.6 mg, 0.03 mmol), 1,3-bis-(diphenylphosphino)-propane (21.3 mg, 0.05 mmol), 4-pentene-1-ol (51.7 mg, 0.60 mmol) and diisopropylammonium-tetrafluoroborate (142 mg, 0.75 mmol) are weighed into a reaction vial. 1,4-Dioxane (1 ml) is added and the reaction vial is flushed with nitrogen. The resulting suspension is stirred for 1 minute, triethylamine (208 μl, 1.50 mmol) is added and the reaction vial is flushed with nitrogen and closed. The reaction mixture is stirred overnight at 110° C. The reaction mixture is allowed to cool to room temperature. n-Heptane (1.5 ml) and tetrafluoroboric acid (0.21 ml, 54% solution in diethylether, 1.5 mmol) are added and the resulting biphasic mixture is stirred vigorously at room temperature for 3 hours. Triethylamine (69 μl, 0.5 mmol) is added and the reaction mixture is then partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 7-fluoro-3-[4-(2-methyl-tetrahydro-furan-2-yl)-phenyl]-2H-isoquinolin-1-one as white powder; HPLC/MS 2.78 min. (B), [M+H] 324; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.58 (s, 1H), 7.85 (dd, J=9.5, 2.8 Hz, 1H), 7.80 (dd, J=8.8, 5.3 Hz, 1H), 7.77-7.71 (m, 2H), 7.62 (td, J=8.7, 2.8 Hz, 1H), 7.53-7.46 (m, 2H), 6.95 (s, 1H), 3.94 (td, J=7.8, 6.4 Hz, 1H), 3.83 (td, J=8.0, 5.7 Hz, 1H), 2.11 (ddd, J=12.0, 8.0, 5.7 Hz, 1H), 2.04 (dt, J=11.9, 7.4 Hz, 1H), 1.97 (dtt, J=15.4, 7.7, 5.6 Hz, 1H), 1.74 (dqd, J=12.0, 7.6, 6.4 Hz, 1H), 1.46 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]3[CH2:11][CH:10]([C:12]#[N:13])[C:7]=3[CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]3[CH2:11][CH:10]([C:12]#[N:13])[C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#CC1Cc2cc3cc[nH]c3cc21
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CC1Cc2cc3c(cc21)NCC3
Temperature: 13 °C
Reaction time: 2 h

Procedure:
3.43 g of the product obtained in Step 4 are dissolved in 55 ml of acetic acid. In the course of 5 minutes, 3.84 g of sodium cyanoborohydride are added in portions to the reaction mixture, which has been cooled to 13° C. After returning to ambient temperature, stirring is carried out for 2 hours, and then the reaction mixture is cooled to 0° C. and the pH is adjusted to 11 by the addition of a solution of sodium hydroxide (45 g in 250 ml of water). The milky solution obtained is extracted with ether. The organic phases are washed, dried and concentrated to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:30])[CH:3]=1.[H-].[Na+].Cl.[CH3:34][N:35]([CH2:37][CH2:38]Cl)[CH3:36].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH2:38][CH2:37][N:35]([CH3:36])[CH3:34])=[C:4]([F:30])[CH:3]=1
Reactant: CN(C)CCCl
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)CCn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (100 mg, 0.22 mmol) was dissolved in DMF (0.5 ml) and cooled in an ice bath. Sodium hydride (60% dispersion, 22 mg, 0.56 mmol) was carefully added. The mixture was stirred for 10 min then dimethylaminoethyl chloride hydrochloride (36 mg, 0.25 mmol) and potassium iodide (4 mg, 0.022 mmol) were added and the reaction was warmed to room temperature then stirred at 50° C. overnight. After cooling to room temperature, water and ethyl acetate were added to the reaction. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed water and sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 46 mg (40%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-4-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. (M+H)+=517.