Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]P(OCC)(OCC)=O)=[CH:7][CH:6]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:31][C:32]1([CH3:50])[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[C:37]2[CH2:36][C:35]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH:43]=O)[CH2:34][C:33]1=2.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:43]/[C:35]2([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:34][C:33]3[C:32]([CH3:31])([CH3:50])[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[C:37]=3[CH2:36]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC1(/C=C/c2ccc(C(=O)OCC)cc2)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
0.7 g of 4-(diethoxy-phosphorylmethyl)-benzoic acid ethyl ester were dissolved in 10 ml of THF and treated at −20° C. with 2.2 ml of a 1 molar solution of lithium bis(trimethylsilyl)amide in hexane. After 15 minutes a solution of 0.46 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde in 5 ml of THF was added. The reaction mixture was stirred for 3 hours at room temperature, poured on ice cold, saturated aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried (Na2SO4) and the solvent evaporated. The yellow, oily residue was purified with flash chromatography (silica gel, hexane/10% ethyl acetate) and gave 0.73 g of (E)-4-[2-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-yl)-vinyl]-benzoic acid ethyl ester as colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41](Br)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22](=[O:49])[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([O:32][C:33]2[C:34]3[C:41]([C:14]4[CH:15]=[CH:16][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=4)=[C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[O:39][C:35]=3[N:36]=[CH:37][N:38]=2)[CH2:27]1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COC(=O)CCCN1CCC[C@H](Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CCc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H]4CCCN(CCCC(=O)OC)C4)c23)cc1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
Add 5.2 mg (0.007 mmol) of bis(triphenylphosphine)palladium(II) chloride,. 30.6 mg (0.221 mmol) of potassium carbonate, 0.04 ml of methanol and 31 mg (0.207 mmol) of 4-ethylbenzeneboronic acid successively under argon to a solution of 70 mg (0.148 mmol) of (+)-4-{(3S)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-1-yl}butanoic acid methyl ester in 0.4 ml of DMSO. Stir the mixture at 80° C. for a total of 3.5 h. After cooling, purify the reaction mixture directly by preparative RP-HPLC (eluent: acetonitrile/water gradient). 37.3 mg (50.6% of theory) of the target compound are isolated.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@:9]([Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:10])[C@@H:8]([CH:28]([Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:29])[O:7][C@H:6]1[N:47]1[C:57]2[N:56]=[C:54]([NH2:55])[NH:53][C:51](=[O:52])[C:50]=2[N:49]=[CH:48]1)[CH:2]=C.C[N+]1([O-])CC[O:62]CC1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Os](=O)(=O)(=O)=O.CC(C)=O>[OH:62][CH2:2][CH2:1][O:4][C@@H:5]1[C@:9]([Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([OH:10])[C@@H:8]([CH:28]([Si:30]([C:43]([CH3:46])([CH3:44])[CH3:45])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[OH:29])[O:7][C@H:6]1[N:47]1[C:57]2[N:56]=[C:54]([NH2:55])[NH:53][C:51](=[O:52])[C:50]=2[N:49]=[CH:48]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCO[C@H]1[C@H](n2cnc3c(=O)[nH]c(N)nc32)O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@]1(O)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OCCO)[C@@]1(O)[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.5 %

Procedure:
2′-O-allyl-3′,5′-bis(tert-butyl diphenylsilyl)guanosine (9 g, 11.23 mmol) was dissolved in CH2Cl2 (80 mL). To the clear solution acetone (50 mL), 4-methyl morpholine-N-oxide (1.89 g, 16.17 mmol) was added. The reaction flask was protected from light. Thus 4% aqueous solution of osmium tetroxide was added and the reaction mixture was stirred at room temperature for 6 hr. Reaction volume was concentrated to half and ethyl acetate (50 mL) was added. It was then washed with water (30 mL) and brine (30 mL). Ethyl acetate layer was dried over anhydrous Na2SO4 and evaporated to dryness. Residue was then dissolved in CH2Cl2 and NaIO4 adsorbed on silica (21.17 g, 2 g/mmol) was added and stirred with the reaction mixture for 30 min. The reaction mixture was filtered and silica was washed thoroughly with CH2Cl2. Combined CH2Cl2 layer was evaporated to dryness. Residue was then dissolved in dissolved in 1M pyridinium-p-toluene sulfonate (PPTS) in dry MeOH (99.5 mL) under inert atmosphere. To the clear solution sodium cyanoborohydride (1.14 g, 18.2 mmol) was added and stirred at room temperature for 4 hr. 5% aqueous sodium bicarbonate (50 mL) was added to the reaction mixture slowly and extracted with ethyl acetate (2×50 mL). Ethyl acetate layer was dried over anhydrous Na2SO4 and evaporated to dryness. Residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to givet the title compound (6.46 g, 72% yield). MS (Electrospray−) m/e 802 (M−H⊕)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2].[CH3:28][O:29][C:30]1[C:31]([O:50][CH3:51])=[C:32]([CH:47]=[CH:48][CH:49]=1)[C:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)C>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:32]3[CH:47]=[CH:48][CH:49]=[C:30]([O:29][CH3:28])[C:31]=3[O:50][CH3:51])=[O:17])[C:8](=[O:9])[C:7]2=[CH:26][CH:27]=1)([OH:3])=[O:2]
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: O=C(NCCN1C(=O)c2ccc(C(=O)O)cc2C1=O)OCCCCCCO
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cccc(C(OCCCCCCOC(=O)NCCN2C(=O)c3ccc(C(=O)O)cc3C2=O)(c2ccccc2)c2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an argon atmosphere, 1.02 g (2.70 mmol) of 1-[(4-carboxyphthalimidylethyl)aminocarbonyl]oxy-6-hexanol (compound 3a) was dissolved in 27 ml of pyridine. To the solution, 915 mg (2.70 mmol) of dimethoxytrityl chloride was added, and the mixture was stirred at room temperature. After 2 hours, 440 mg (1.30 mmol) of dimethoxytrityl chloride was further added to the reaction solution, and the mixture was stirred at room temperature for additional 2 hours. 5 ml of ethanol was added to the reaction solution, and the mixture was then concentrated under reduced pressure. The residue was dissolved in 150 ml of chloroform. The solution was washed with 50 ml of water twice and 50 ml of saturated saline once and dried over sodium sulfate. The solution was concentrated under reduced pressure, followed by azeotropy with 5 ml of toluene. The residue was purified by silica gel column chromatography (elution solvent: ethanol-chloroform, containing 0.3% pyridine) to obtain 1.88 g (pyridine salt, yield: 92%) of the title compound (compound 4a) as a yellow foam.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:20][N:21]3[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]3=[O:29])=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:12]=1>FC(F)(F)C(O)=O>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:20][N:21]3[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]3=[O:29])=[C:14]([C:16]([F:18])([F:17])[F:19])[N:15]=2)[N:12]=1
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(NCc4ccc(OC)cc4OC)nn23)C1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(N)nn23)C1
Yield: 11 %

Procedure:
1-{[6-[(2,4-dimethoxybenzyl)amino]-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one x268 (396 mg, 0.83 mmol) is stirred at room temperature in trifluoroacetic acid until its complete consumption (17 hours). After TFA removal under reduced pressure, the residue is taken in saturated K2CO3 aqueous solution and extracted with ethyl acetate (3×15 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure to yield the crude material which is purified by reverse phase preparative chromatography (gradient acetonitrile/water/TFA) to afford 1-{[6-amino-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 53.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N:18](C)[C:19](=O)C(F)(F)F)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:26])[C:6]([C:27]([O:29]C)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1>CC(O)=O.Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)c(N(C)C(=O)C(F)(F)F)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CNc1c(F)c(F)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of methyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-(N-methyltrifluoroacetamido)-4-oxoquinoline-3-carboxylate (880 mg, 2.03 mmol) in AcOH (10 mL), 6M HCl (5 mL) was added. The mixture was stirred at 100° C. for 4 h. After cooling, the solvent was removed by evaporation. 50 mL water was added, and the resulting precipitate was collected by filtration, washed with water and dried to give 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methylamino-4-oxoquinoline-3-carboxylic acid (605 mg, 92%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]4[N:24]=[C:23]([CH:25]5[CH2:28][C:27]([F:30])([F:29])[CH2:26]5)[O:22][N:21]=4)[CH:17]=[CH:16][C:15]=3[CH3:31])=[O:12])=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[F:29][C:27]1([F:30])[CH2:28][CH:25]([C:23]2[O:22][N:21]=[C:20]([C:18]3[CH:17]=[CH:16][C:15]([CH3:31])=[C:14]([NH:13][C:11]([C:8]4[N:6]5[CH:7]=[C:2]([C:40]6[CH:41]=[N:42][NH:43][CH:44]=6)[CH:3]=[CH:4][C:5]5=[N:10][CH:9]=4)=[O:12])[CH:19]=3)[N:24]=2)[CH2:26]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(-c3cn[nH]c3)cn12
Temperature: 130 °C

Procedure:
6-Bromo-N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (42a) (98.0 mg, 0.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (60.0 mg, 0.3 mmol), K3PO4(42.0 mg, 0.2 mmol) and Pd(PPh3)4(46.2 mg, 0.04 mmol) were added to a flask equipped with a stir bar. The flask was evacuated and backfilled with nitrogen several times. 1,4-Dioxane (1 mL) and the reaction was heated at 130° C. for 20 minutes in a microwave reactor. The reaction was filtered and purified by preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (F40). MS m/z 476.1 (M+1)+.
Reaction SMILES: [H-].[Li+].[O:3]=[C:4]1[NH:9][CH:8]=[CH:7][N:6]=[C:5]1[C:10]([O:12][CH3:13])=[O:11].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([N:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ncc[nH]c1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nccn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiH was added to the solution of methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate (0.10 g, 0.65 mmol) in DMF (3 mL) at 0° C. After stirring for 30 minutes, benzyl chloride (0.15 mL, 1.30 mmol) was added to the reaction mixture at the temperature, and the reaction was warmed to room temperature. After stirring for 3 days, the reaction mixture was diluted with EtOAc, quenched with ice water, extracted with EtOAc, dried over MgSO4, and concentrated to give the desired product, which was purified by silica gel flash column chromatography (2% MeOH in CH2Cl2, 0.102 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.35-7.40 (m, 6H), 7.29 (d, 1H), 5.14 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1.[O-:22]Cl=O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:14])=[O:22])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A 2 L flask was charged with 37.31 g of 1-(2-chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole (119 mmol), 470 mL of acetonitrile, then a solution of NaH2PO4 (71.49 g in 174 mL of water) was added. The resulting solution was cooled to 0-30C in an ice bath and a NaClO2 solution (80%, 107.84 g in 391 mL of water) was added portionwise. The resulting solution was allowed to warm to room temperature where it remained for 42 h. The reaction was then concentrated in vacuo to remove acetonitrile. The residue was washed into a separatory funnel with 525 mL of 2.0 M NaOH and CH2Cl2. The CH2Cl2 was separated and was washed twice with 2.0 M NaOH. The NaOH washings were combined, acidified with concentrated HCl, and were extracted with CH2Cl2. The CH2Cl2 was then concentrated in vacuo and the crude acid was precipitated from CH2Cl2 with hexanes. 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid was recovered as a tan solid, yield: 20.1 g (58%); 1H NMR (400 MHz, DMSO-d6): δ 14.1 (s, 1H), 7.86-7.90 (m, 2H), 7.80 (dt, J=1.5, 7.5 Hz, 1H), 7.76 (s, 1H), 7.73 (dt, J=1.5, 7.5 Hz, 1H); MS (ES): 291 [M+H]+.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]1[C:22]3[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=3[S:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]1[C:22]3[CH:21]=[CH:20][C:19]([C:24]#[N:25])=[CH:18][C:17]=3[S:16][C:15]3[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2]2
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)Sc1ccccc1N2C1CC2CCC(C1)N2
Temperature: 160 °C

Procedure:
To a solution of 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-10H-phenothiazine, 4i (50 mg, 0.13 mmol) in DMF (750 μL) was added zinc cyanide (15 mg, 0.13 mmol) and tetrakistriphenylphosphine palladium (4 mg), the solution was purged with nitrogen, and the mixture was heated in the microwave for 5 min at 160° C. The mixture was allowed to cool to rt, and purified via reverse phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield title compound 10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile, 1aa as a TFA salt and as a mixture of endo and exo isomers. MS m/z (MH+) 334.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:6]4[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:19][CH:18]=2)[S:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: Cc1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2ccc(-c3cnc4ccc(Br)cn34)cc2)n1
Yield: 48.3 %

Procedure:
159 mg of 4-(6-bromoimidazo[1,2-a]pyridin-3-yl)benzoic acid (compound in Production Example 54), 58 mg of 2-amino-4-methyl-1,3-thiazole, 243 mg benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 83 μL triethylamine were reacted overnight in 4 mL dichloromethane. The reaction solution was purified by an NH silica gel column, to give 100 mg of the title compound (pale yellow crystals; recrystallization solvent, ethyl acetate-methanol).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccc(F)c3)C2=O)CC1
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-fluorobenzyl bromide, to give the desired product as a white solid (79%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:11]=1)=[O:13]
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Cl)c2cccnc2c1O
Reactant: C1COCCN1
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(N2CCOCC2)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A solution of the chloride from Example 44 Step 5 (14 mg, 0.037 mmol) in morpholine (0.5 ml) was heated at 120C for 36 hrs under argon. The resulting solution was cooled to room temperature and the solvent evaporated in vacuo. The residue was dissolved in hot DMF (0.5 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
To a solution of methyl 5-chloroanthranilate (10.50 g (56.6 mmol) in pyridine (30 ml), p-toluenesulfonyl chloride (12.00 g (62.9 mmol)) was added with stirring at 5° C. The mixture was stirred at room temperature for 18 hours, and then, 200 ml of water was added to the resulting mixture. The crystals separated were filtered and washed to give 18.20 g (95%) of 4′-chloro-2′-methoxycarbonyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [Na].[H-].COCCO[Al+2].[H-].[OH:10][CH:11]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12]#[C:13][C:14]1[N:19]=[C:18]([CH2:20][C:21]2[O:26][C:25](=[O:27])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[OH:10][CH:11]([CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:12][CH2:13][C:14]1[N:19]=[C:18]([CH2:20][CH:21]([OH:26])[CH2:22][CH2:23][CH2:24][CH2:25][OH:27])[CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCCCC(O)C#Cc1cccc(Cc2cccc(=O)o2)n1
Agent: COCCO[Al+2]
Agent: [H-]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCCCCC=CCC(O)CCc1cccc(CC(O)CCCCO)n1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
Sodium (bis) 2-methoxyethoxy-aluminum hydride (0.52 ml, 1.78 mmole) is dissolved in 2 ml dry toluene in an oven-dried 50 ml 2-neck round bottom flask under nitrogen at 0° C. 6-[1-[6-(3-Hydroxy-undec-1ynyl)-pyridine-2yl]-methyl-]pyran-2-one (160 mg, 0.445 mmole), in 2×1 ml dry toluene, is added slowly dropwise to the reaction mixture at 0° C. The mixture is stirred 7 hours at 0° C., quenched with 0.100 ml water, and stirred vigorously overnight with 10 ml 0.5M sodium potassium tartrate. The mixture is extracted with 4×10 ml ethyl acetate. The combined organics are dried over magnesium sulfate and concentrated in vacuo to a pale oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirred solution of 5-chloro-N-{2-ethyl-1-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.30 g, 0.66 mmol) in CH2Cl2 (10 mL) at −78° C. was added a solution of boron tribromide (1.0 M, 0.99 mL, 0.99 mmol) dropwise. After 4 h at −78° C. and 18 h at room temperature, another 1.5 eq BBr3 (0.99 mL) was added at −78° C. The reaction mixture was gradually warmed to room temperature and stirred for 18 h. The reaction mixture was slowly poured into H2O and extracted with CH2Cl2 (3×'s), dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude solid was purified by column chromatography (SiO2, EtOAc/hexane, 2:3), then precipitated with Et2O/hexane to yield a white solid in 34% yield.