Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:11][C:5]2=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=[C:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.O>CN1C(=O)CCC1>[Cl:10][C:7]1[N:6]=[C:5]2[NH:11][C:2]([N:12]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:26])[O:18]4)[CH2:14][CH2:13]3)=[N:3][C:4]2=[CH:9][CH:8]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: Clc1ccc2nc(Cl)[nH]c2n1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC2(CCN(c3nc4ccc(Cl)nc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2,5-dichloro-3H-imidazo[4,5-b]pyridine (0.07 g, 0.37 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.15 g, 0.74 mmol) in dry NMP (3 mL) at 100° C. for 14 hours. Pour the cooled mixture into water (10 mL) and extract twice with EtOAc (10 mL). Wash the combined extracts with brine (10 mL), dry, and evaporate in vacuo. Purify by preparative TLC (5% MeOH—CH2Cl2) to obtain 1′-(5-chloro-3H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A solution of Pd(PPh3)4 (Strem Chemicals Inc., Newburyport, Mass., 0.804 g, 0.696 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (Matrix Scientific, Columbia, S.C., 3.05 g, 8.70 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.500 g, 6.96 mmol), and potassium carbonate (4.81 g, 34.8 mmol) in 14 mL dioxane and 6 mL water was heated to 100° C. overnight. LC/MS showed about 50% conversion, so the reaction mixture was transferred to a microwave vial, and was heated to 130° C. in a microwave reactor for 3 hours. The reaction mixture was diluted with EtOAc, washed with water then brine, the organics dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 30% EtOAc/heptane) gave tert-butyl 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.73 g, 5.98 mmol).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].Br.Br.Br.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:19]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-:32].[Na+].[Na+]>CN(C)C=O>[OH2:32].[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:2][C:3]#[N:4])[CH2:13][CH2:12]2)[CH:22]=1.[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:19]2[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=[C:15]2[NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:2][C:3]#[N:4])[CH2:13][CH2:12]2)[CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCCl
Reactant: c1cncc(Cn2c(NC3CCNCC3)nc3ccccc32)c1
Agent: Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CCC(Nc2nc3ccccc3n2Cc2cccnc2)CC1
Product: O
Temperature: 50 °C
Yield: 50 %

Procedure:
A mixture of 2.7 parts of 2-chloroacetonitrile, 19.5 parts of N-(4-piperidinyl)-1-(3-pyridinylmethyl)-1H-benzimidazol-2-amine trihydrobromide, 13 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated for 3 hours at 50° C. The reaction mixture was poured onto water and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 6 parts (50%) of 4-[[1-(3-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile hemihydrate; mp. 204.5° C. (intermediate 73).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16].[NH2:23][NH2:24]>C(O)(C)C>[CH2:15]([N:17]1[CH2:22][CH2:21][N:20]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:23][NH2:24])[CH:7]=2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: NN
Reactant: Clc1cc(Cl)ncn1
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCN1CCN(c2cc(NN)ncn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.8 %

Procedure:
Dissolve 4,6-dichloropyrimidine, (1.1 g, 7.4 mmol), in 20 mL isopropanol, add potassium carbonate, (2 g, 15 mmol), and N-ethylpiperazine, (843 mg, 7.4 mmol). Stir at rt for 18 h, then add hydrazine, (1.6 g, 50 mmol) and heat to reflux for 22 h. Cool and filter, then evaporate the solvent from the filtrate. Take up the residue in 20 mL boiling acetonitrile and filter. Upon cooling, a white precipitate forms. Filter to obtain approx 1 g [6-(4-Ethyl-piperazin-1-yl)-pyrimidin-4-yl]-hydrazine as a white solid. (60%). MS ES+ 223.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=O)[CH2:34][NH:35][C:36]([CH:38]4[CH2:42][C:41]5([CH2:47][CH2:46][S:45](=[O:49])(=[O:48])[CH2:44][CH2:43]5)[CH2:40][N:39]4[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=O)=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:67]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][CH:6]([CH3:8])[C@H:5]([NH:4][C:3](=[O:62])[O:2][CH3:1])[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[N:67]=[C:36]([CH:38]5[CH2:42][C:41]6([CH2:43][CH2:44][S:45](=[O:49])(=[O:48])[CH2:46][CH2:47]6)[CH2:40][N:39]5[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:53])[CH3:54])[NH:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[N:20]=1)=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 110 °C
Yield: 37.9 %

Procedure:
A solution of methyl((1S)-2-methyl-1-{[(2S)-2-(4-{4′-[({[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-8,8-dioxido-8-thia-2-azaspiro[4.5]dec-3-yl]carbonyl}amino)acetyl]-4-biphenylyl}-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}propyl)carbamate (108) (107 mg, 0.12 mmol) and ammonium acetate (94 mg, 1.2 mmol) in dioxane (1.5 mL) was degassed with nitrogen and heated to 110° C. in a sealed tube for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate and filtered and concentrated in vacuo. Purified by SFC to afford the product as a tan solid (39 mg, 37% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.32 (br. s., 2H) 5.05-5.24 (m, 1H) 4.04-4.29 (m, 1H) 3.99 (br. s., 1H) 3.81 (br. s., 1H) 3.55-3.73 (m, 6H) 3.03-3.25 (m, 4H) 1.80-2.47 (m, 14H) 0.68-1.06 (m, 16H). HRMS for C44H57N8O8S (M+H)+ calc: 857.4020. found: 857.4020. Purity (LC-MS): 97%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C.C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[N:5][CH:4]=[C:3]([NH:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CNc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.7 %

Procedure:
To 76 mg of (7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, a solution of 0.11 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 2.5 mL of dichloromethane and 19 μL of acetic acid were added, and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture, 0.10 g of sodium triacetoxyborohydride was added, and the mixture was stirred at the same temperature for 2 hours 20 minutes. Thereto was added chloroform and the reaction mixture was adjusted to pH 8.3 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=19:1 to obtain 55 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(methylamino)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)c1
Yield: 87.9 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.2 mg (0.059 mMol) 3-methylbenzoyl chloride, 17.1 mg (88%) of the title compound were recovered.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[C:4]1([CH3:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:12]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])[CH2:11][CH2:10][CH2:14][O:13]1
Reactant: C1CCOC1
Reactant: Cc1ccccc1Br
Agent: [Mg]
Product: Cc1ccccc1C1(c2ccccc2C)CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium turnings (33 g) in dry THF (150 mL) was added 2-bromotoluene (4 ml ). The reaction mixture was heated to reflux and an exotermic reaction started. The heating mantle was removed and 2-bromotoluene (137 mL) in dry THF (500 mL) was added dropwise over an hour at reflux temperature (exotermic reaction). The resulting reaction mixture was boiled under reflux for additionally 1.5 hrs. The mixture was cooled to room temperature and excess Mg was filtered off in an inert atmosphere. A solution of 4-chlorobutyric acid methylester (56.4 g) in dry THF (200 mL) was added dropwise at 20° C. The reaction mixture was stirred at room temperature for additionally 1 hr and was then poured into an aqueous solution of NH4Cl and ice. The organic phase was worked-up according to the standard workup procedures. After evaporation of the organic solvent the residue was suspended in a mixture of n-heptane/ethyl acetate=4/1. Filtration of the resulting crystals afforded 2,2-di-(2-tolyl)-tetrahydrofuran 33a (32.5 g). 1H NMR (CDCl3) δ1.96 (s,6H), 1.96-2.10 (m,2H), 2.57 (t,2H), 4.02 (t,2H), 7.00-7.07 (m,2H), 7.07-7.23 (m,4H), 7.57-7.65 (m,2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.[Cl:31]C(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([CH3:49])[N:48]=1>C(Cl)(Cl)Cl.O>[ClH:31].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:43][C:44]2[S:45][CH:46]=[C:47]([CH3:49])[N:48]=2)=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)cs4)c(F)c3)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (10 g) was dissolved in chloroform (300 ml) and triethylamine (40 ml) to prepare a solution. A solution of triphosgene (10 g) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 30 min. Next, 2-amino-4-methylthiazole (4.36 g) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous magnesium sulfate. The dried organic layer was filtered and was then concentrated, and ether was added to the residue for crystallization, followed by collection of the resultant crystal by filtration. The crystal was purified by chromatography (chloroform:acetone=2:1). A 10% solution of hydrogen chloride in methanol was added to the purification product, followed by concentration. The resultant crystal was washed with ether to give 6.0 g of the title compound.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH:28](CC[O-])[CH:29]([C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[OH-].[Na+]>O>[OH2:15].[N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH2:28][CH:29]([C:30]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c1cc(F)cc3C(CC[O-])C2C(=O)N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c(cc(F)cc31)CC2C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Heat a slurry of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine ethanolate (198.5 mg) in water (10 mL) to 80° C. for 2.75 hours. Add 3.11 mL of 1N HCl. When the temperature has returned to 80° C., rapidly add 3.11 mL of 1N NaOH. Allow the temperature to remain at 80° C. for approximately 15 minutes then allow the suspension to cool to room temperature. Collect the solid using vacuum filtration through Whatman #1 paper and allow to dry loosely covered over night. Powder X-ray Principal Peaks (Degrees 2 Theta, Intensity): 12.089°, 100%; 10.485°, 83.6%; 13.227°, 56.0%; and 7.660°, 8.0%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17](OCC)=[O:18])=[C:13]([OH:22])[C:12]([CH:23]([CH3:25])[CH3:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].BrCC1C=CC=C(C#[N:37])C=1.Cl.CC[O:41][C:42]([CH3:44])=[O:43]>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:15](=[O:16])[C:14]([C:17]([NH:37][CH2:44][C:42]([OH:41])=[O:43])=[O:18])=[C:13]([OH:22])[C:12]([CH:23]([CH3:24])[CH3:25])=[N:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc(CBr)c1
Reactant: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2cccc(C#N)c2)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(Cc2cccc(C#N)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Ethyl 2-[(3-cyanophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. Sodium hydride (53 mg, 1.33 mmol) was added to a solution of the compound from example 14a) (120 mg, 0.53 mmol) in N,N-Dimethylformamide (DMF) (2.5 mL) at 0° C. The reaction was brought to room temperature and stirred for 30 minutes. The temperature was then reduced to 0° C. and α-bromo-m-tolunitrile (104 mg, 0.53 mmol) was added. The reaction was brought to room temperature and stirred for 3 h followed by the addition of 1N HCl. The solution was diluted with EtOAc and H2O and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 30-60% EtOAc/Hexanes) to give the title compound (95 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (s, 1H) 7.78 (dt, J=6.88, 1.74 Hz, 1H) 7.72 (s, 1H) 7.52-7.63 (m, 2H) 5.20 (s, 2H) 4.27 (q, J=7.16 Hz, 2H) 3.16 (sept, J=6.82 Hz, 1H) 1.26 (t, J=7.07 Hz, 3H) 1.16 (d, J=6.82 Hz, 6H).
Reaction SMILES: CN(C)C(=O)C.C1([SH:13])C=CC=CC=1.Br[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[OH-].[K+]>[C:24]1([C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[S:13])=[CH:22][CH:23]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Sc1ccccc1
Reactant: c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: OC(=S)c1ccc(-c2ccccc2)cc1
Temperature: 150 °C

Procedure:
A solution of 70 ml of N,N-dimethylacetamide in which 20.86 g of potassium hydroxide was dissolved was heated to 150° C., and 19.52 ml of thiophenol and 25.47 g of 4-bromobenzoic acid were added under nitrogen atmosphere while stirring at the same temperature. After reflux for 20 hours under nitrogen atmosphere, the reaction mixture was poured into 400 ml of ice water, and 400 ml of benzene was added to wash, and the water layer was separated. The benzene layer was extracted with 2.5N sodium hydroxide (100 ml×4). The extract was combined with the water layer and the pH was adjusted to 1 to 2 with concentrated hydrochloric acid, and the precipitate was filtered, washed in water, dried, and 4-phenylthiobenzoic acid was obtained (26.29 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]([CH2:8][Cl:9])=[CH2:7].[FH:10]>>[Cl:5][C:6]([F:10])([CH2:8][Cl:9])[CH2:7][N+:1]([O-:4])=[O:2]
Reactant: F
Reactant: O=[N+]([O-])O
Reactant: C=C(Cl)CCl
Product: O=[N+]([O-])CC(F)(Cl)CCl
Reaction time: 1 h

Procedure:
To a mixture of 86 ml of anhydrous, 100% strength nitric acid and 300 ml of anhydrous hydrofluoric acid were added dropwise at -10° C. in the course of 3 hours 111 g (1 mol) of 2,3-dichloropropene. The reaction was slightly exothermic. After the dropwise addition had ceased, stirring was continued for a further 1 hour at -10° C. Then the mixture was poured on to ice and extracted using dichloromethane. The organic phase was washed with sodium hydrogencarbonate solution, dried over sodium sulphate and concentrated using a rotary evaporator. The crude product was distilled under an oil pump vacuum. This gave 115.8 g (=63% of theory) of product having a boiling point of 48° to 50° C. at 0.07 mbar and a Refractive Index nD20 of 1.4578 (at 24° C.). The product was 95.7% pure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6]1[O:14][CH:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCO.N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:14])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(C2CO2)cc1
Reactant: c1c[nH]cn1
Solvent: CCO
Solvent: c1ccncc1
Product: OC(Cn1ccnc1)c1ccccc1
Yield: 35.2 %

Procedure:
A solution of 17.6 g (0.258 mole of imidazole in 100 mL of absolute EtOH was treated with 0.6 mL (4.0 mmol) of pyridine and refluxed for 25 minutes. This was then treated dropwise with a solution of 31.06 g (0.258 mol) of styrene oxide and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken tip in Et2O and washed with H2O. A solid separated which was collected and dissolved in warm CHCl3/EtOAc. The organic phase was washed with saturated NaCl and dried over MgSO4. Treatment of the filtrate with charcoal, filtering, and concentrating to 1/3 volume caused a solid to separate. There was collected 17.09 g (35% yield) of the product as a white solid, mp 146-148° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 189 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.C[N:22]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:22][NH:23][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: Cn1cc(B(O)O)cn1
Product: COc1cccc2c(-c3cn[nH]c3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and N-methyl-pyrazole-4-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-5-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH3:12])([CH3:11])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH3:11])([CH3:12])[O:9][C:8](=[O:13])[N:7]([CH3:15])[C:6]=2[CH:14]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C)OC(=O)Nc2cc(Br)ccc21
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)OC(C)(C)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
Into the solution of 7-bromo-4,4-dimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.37 (1.35 g) in DMF (20 mL) was added 1M solution of NaHMDS in THF (7 mL) at rt. After 30 min., MeI (0.85 g) was added. After overnight stirring, the reaction mixture was extracted with ethyl acetate and washed with brine, and dried with dry agent. After removal of the solvent, the residue was crystallized from mixture of DCM and Hexane to provide 1.2 g of 7-bromo-1,4,4-trimethyl-1H-benzo[d][1,3]oxazin-2(4H)-one 7.38 was synthesized.