Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.C([O-])([O-])=O.[K+].[K+].[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][CH:28]=1)=[O:26].O>CS(C)=O>[CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[N:8]3[C:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH3:24])=[CH:28][CH:29]=1
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11H-benzo[a]carbazole (2.00 g, 9.22 mmol) in DMSO (20 mL) is added K2CO3 (3.85 g, 27.9 mmol) at 180° C., and then the mixture is stirred for 1 hour. To the mixture is added 4-fluoroacetophenone (1.28 g, 9.228 mmol). After stirring for 8 hours, the reaction mixture is cooled to room temperature, and poured into water. The crude product is extracted with ethyl acetate, and it is washed with water and brine. The organic layer is dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (160 mg; 5%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 2.75 (s), 7.20 (d), 7.23 (t), 7.34-7.46 (m), 7.65 (d), 7.75 (d), 8.00 (d), 8.19 (d), 8.22 (d), 8.25 (d).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=O)C.O.[CH2:22](O)[CH3:23].C(Br)C>[OH-].[Na+]>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[C:10]([C:15]([OH:17])=[O:16])=[CH:11][N:12]2[CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cnc2cc(NC(C)=O)ccc2c1O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCBr
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N)cc21

Procedure:
4.6 Grams of ethyl 7-acetamido-4-hydroxy-3-quinolinecarboxylate are dissolved in 15 ml of 10% NaOH, 60 ml of H2O and 100 ml of ethanol, and 5 ml of ethyl bromide are added. The mixture is left under reflux for 4 hours, then the excess of ethyl bromide and ethanol is evaporated off, and 10 ml of 10% NaOH are then added. The mixture is heated under reflux for 2 hours, allowed to cool, acidified with HCl, filtered and treated with ethanol at 70° C. The product is filtered off and recrystallized in a dimethylformamide/water (1:1) mixture. 1.0 Gram of a solid is obtained, of melting point 304°-307° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2.[BrH:12]>>[BrH:12].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2
Reactant: COc1ccc2c(c1)CNC2
Agent: Br
Product: Oc1ccc2c(c1)CNC2
Temperature: 25 °C
Yield: 93 %

Procedure:
5-Methoxyisoindoline (8.34 g, 55.97 mmol) in 48% aqueous hydrobromic acid (100 ml) was stirred and held at reflux for 16 hours. Upon cooling to room temperature the solvent was removed in vacuo to afford 5-hydroxyisoindoline hydrobromide (11.32 g, 93%) as a tan solid. 1H NMR (DMSO-d6) 9.63 (1H, br s), 9.32 (2H, br s), 7.18 (1H, d), 6.79 (1H, d), 6.76 (1H, dd), 4.42 (2H, t), 4.38 (2H, t). MS: [M+H]+ 136.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([C:8]1([CH2:12][C:13]2[S:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)=O)C.CO.[OH-].[Na+]>CCOCC>[Cl:18][C:15]1[S:14][C:13]([CH2:12][C:8]2([CH2:6][OH:5])[CH2:11][CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1(Cc2ccc(Cl)s2)CCC1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: OCC1(Cc2ccc(Cl)s2)CCC1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
Lithium borohydride (718 mg, 33 mmol) was added to a solution of ester 19 (2.9 g, 11.2 mmol) in ether (50 mL) at 0° C. After having stirred for 5 min, MeOH (1.05 g, 33 mmol) was added dropwise and stirring continued at 0° C. until effervescence ceased. The mixture was warmed to 23° C. and was allowed to stir an additional hour, at which time the mixture was poured into NaOH (3N) and stirred. The organic layer was seperated and washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified via FCC (silica gel, 1:1, hexane/CH2Cl2) to give 2.57 g of the above named alcohol 20.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:11][C:12]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=O.[H-].[Na+].S(OC)(OC)(=O)=O>C1COCC1>[CH3:17][O:16][C:14]1[C:13]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:12]=2[O:11][C:2]=1[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1ccccc1CBr
Reactant: COC(=O)c1cc(C)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2C#N)oc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
2-(Bromomethyl)benzonitrile (17.6 g) was added to a mixture of methyl 2-hydroxy-5-methylbenzoate (15 g) and sodium hydride (2.7 g, 80% dispersion in oil) in dry THF (150 ml) and the resulting mixture heated at reflux for 5 h. Further sodium hydride (2.7 g, 80% dispersion in oil) was added and heating continued overnight. The mixture was cooled (0° C.), sodium hydride (2.7 g, 80% dispersion in oil) and dimethyl sulphate (17 ml) were added, and the resulting solution stirred at room temperature for 4 h. Solvent was removed in vacuo, the residue taken up in dichloromethane (200 ml) and cone. ammonia solution (200 ml) added carefully. The organic solution was removed and the aqueous solution extracted with dichloromethane (2×200 ml). The combined, dried organic phases were evaporated in vacuo and the residue purified by chromatography, eluting with dichloromethane: hexane (1:1) to give the title compound as a white solid (17 g).
Reaction SMILES: C([O:8][C:9](=[O:38])[CH2:10][N:11]([C:21](=[O:37])[CH2:22][N:23]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])CC1C=CC=CC=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)C1C=CC=CC=1.[H][H].[ClH:41].CCOCC>C(O)C.[C].[Pd]>[ClH:41].[CH2:35]([O:34][C:32]([CH2:31][NH:23][CH2:22][C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([OH:38])=[O:8])=[O:37])=[O:33])[CH3:36]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CC(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CNCC(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
N-(N'-Ethoxycarbonylmethyl-N'-benzylglycyl)-N-(indan-2-yl)glycine benzyl ester (3 g) is dissolved in 100 ml of ethanol, and catalytic reduction is carried out at ordinary temperature and pressure using 5% palladium-carbon as catalyst. After absorption of 2 equivalents of hydrogen, the reaction mixture is filtered to remove the catalyst. The ethanol is distilled off under reduced pressure to give an oily substance. Addition of ethanolic hydrochloric acid with 100 ml of ether to the oily substance gives N-(N'-ethoxycarbonylmethylglycyl)-N-(indan-2-yl)glycine hydrochloride as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.Cl.Cl.Cl.[N:25]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][C:4]3[CH:18]=[CH:19][C:20]([F:21])=[C:2]([F:1])[CH:3]=3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:38][CH2:39]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 149 (preparation see below) and amine 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[CH:9]([OH:11])[CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[C:9](=[O:11])[CH3:10]
Reactant: COc1nnc(-c2ccncc2)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1C(C)=O
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 0.91 g 1-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-ethanol in 10 ml CH2Cl2 is added a suspension of 1.70 g Dess-Martin Periodane in 10 ml CH2Cl2 at room temperature. After being stirred for 3 h, the suspension is extracted with 5% aq. Na2S2O3 solution. The organic layer is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is purified by chromatography to give 0.83 g (92%) of the desired product as a yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11](=[O:13])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[O:13]=[C:11]1[NH:10][CH:9]=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:3][CH2:4]2)[S:12]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2c[nH]c(=O)s2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3c[nH]c(=O)s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-3H-thiazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][NH:9][CH3:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.N1CCC1=O.C([O-])([O-])=O.[Cs+].[Cs+].C[C:24]1([CH3:64])[C:50]2[C:45](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:44]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:11][C:5]1[CH:6]=[C:7]([CH2:8][NH:9][CH3:10])[C:2]([CH:64]2[CH2:24][CH2:50][C:45]2=[O:44])=[N:3][CH:4]=1
Reactant: CNCc1cc(Br)cnc1Br
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNCc1cc(Br)cnc1C1CCC1=O
Temperature: 90 °C

Procedure:
A solution of (2,5-dibromopyridin-3-yl)-N-methylmethanamine (95 mg, 0.47 mmol), azetidinone (34 mg, 0.47 mmol), Cs2CO3 (308 mg, 0.94 mmol) in 5 mL of toluene was degassed with bubbling argon for 30 min followed by the addition of Pd2(dba)3 (6 mg, 0.01 mmol) and Xantphos (12 mg, 0.02 mmol). The resulting yellow solution was then stirred at 90° C. 18 h. The dark coloured solution was removed from the heat and poured over a pad of celite washing with 50 mL of ethyl acetate. The filtrate was diluted with 50 mL of water, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified using flash chromatography on silica gel using 95% dichloromethane:methanol to obtain the product as a orange sticky solid. Yield 66 mg (73%); 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=4.8 Hz, 1H), 7.28 (d, J=7.2 Hz, 1H), 6.78 (m, 1H), 4.92 (bs, 1H), 4.51 (s, 2H), 3.58 (q, J=6.0 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 2.84 (s, 3H); ESI MS m/z 192 [C10H13N3O+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][N:7]=1)=[O:5])[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccccc2)c1N
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of 4-nitro-5-phenyl-isoxazole-3-carboxylic acid ethyl ester (73.0 mg, 0.278 mmol) in EtOH (2.0 mL) is added Raney Ni and the mixture is stirred under hydrogen (balloon) for overnight. The reaction mixture is then filtered through Celite and evaporated in vacuo to provide crude 4-amino-5-phenyl-isoxazole-3-carboxylic acid ethyl ester (61.7 mg, 95% yield); HPLC-MS calculated for C12H12N2O3 (M+H+) 233.1. Found: 233.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)nc2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc(N)cc2)nc2ccccc12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-(4-nitrophenyl)quinazoline-4-carboxylate (1.2 g, 3.71 mmol, 1.00 equiv), water (13 mL), sodium hydroxide (150 mg, 3.75 mmol, 2.00 equiv) and sodium hyposulfite (1.3 g, 2.00 equiv). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The solids were filtered out. The filter cake was washed with 1×50 mL of ethanol. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 0.8 g (73%) of ethyl 2-(4-aminophenyl)quinazoline-4-carboxylate as a yellow solid. MS (ESI) m/z 294 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:38][C:39]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: COCCOC
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (12.4 g, 23.0 mmol) and 2,4-difluorophenylboronic acid (7.0 g, 46.0 mmol) in degassed dimethoxyethane (620 mL). Add 2M aqueous sodium carbonate (73 mL, 145 mmol) and stir at room temperature under nitrogen for 5 minutes. Add palladium(II) acetate (520 mg, 2.3 mmol) and triphenylphosphine (1.2 g, 4.6 mmol) and plunge into a 85° C. oil bath. Stir for 40 minutes and cool to room temperature. Pour into saturated aqueous sodium bicarbonate and extract twice with methylene chloride. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Purify the resultant oil with SCX columns (load in methanol, elute with 2M NH3/MeOH) to yield 10.8 g (93%) of the title compound: mass spectrum (ion spray) m/z=502.3 (M+H).
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: C1COCCN1
Product: O=C(c1ccccc1)c1[nH]c2cc(Cl)ccc2c1CC(=O)N1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and morpholine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH2:19]([C:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21]>>[CH2:19]([C:22]1([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])[CH2:24][CH2:23]1)[CH:20]=[CH2:21]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: C=CCC1(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)CC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 1-allylcyclopropane-1-sulfonyl chloride to obtain the desired product. m/z=507 [M−1]−.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1.O>C(#N)C>[C:1]([C:23]1[N:32]2[CH:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=[C:31]2[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1)#[N:2]
Reactant: Clc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1nc2c(c3nc(-c4ccccc4)cn13)CCCC2

Procedure:
To a solution of 200 mg of potassium cyanide and 300 mg of 18-crown-6 in 20 mL of acetonitrile was added 5-Chloro-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (220 mg). The mixture was refluxed for 2 hours, cooled and poured into water. The aqueous layer was extracted with dichloromethane, the organic layer separated and dried and the solvent removed in vacuo. The resultant crude reaction mixture was chromatographed using 15% ethyl acetate/hexane as eluent to yield 5-Cyano-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 44), m.p. 203-205° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[C:24](Br)[C:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[C:24]([NH:12][C:3]3[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=3[F:1])[C:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=2)[CH:22]=[N:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Br
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc2c(cnn2C(=O)OC(C)(C)C)c1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A solution of 2-fluoro-4-trimethylsilanyl-phenylamine (1.2 g, 6.5 mmol) in toluene (20 mL) was added to a mixture of 4-bromo-indazole-1,5-dicarboxylic acid di-tert-butyl ester (2.0 g, 5.0 mmol), Pd2 dba3 (114 mg, 2.5 mol %), Xantphos (144 mg, 5 mol %) and potassium phosphate tribasic (1.49 g, 7 mmol) under nitrogen. The atmosphere was evacuated and back-filled with nitrogen and then the reaction mixture heated at 90° C. for 18 hours. The cooled reaction mixture was diluted with ethyl acetate, filtered through Celite®, and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, dry loading on HM-N, gradient 0 to 10% ethyl acetate in cyclohexane) to give the title compound as an orange gum (1.9 g, 76%). 1H NMR (CDCl3, 400 MHz) 10.03 (1H, s), 8.05 (1H, d, J=9.03 Hz), 7.57 (1H, dd, J=9.00, 0.83 Hz), 7.28-7.18 (4H, m), 1.68 (9H, s), 1.63 (9H, s), 0.28 (9H, s).
Reaction SMILES: [Na].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([C:26]([OH:28])=[O:27])[CH2:17][S:18]CC2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].N.[Cl-].[NH4+]>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([C:26]([OH:28])=[O:27])[CH2:17][SH:18])[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(CSCc2ccccc2)C(=O)O)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC(CS)C(=O)O)CC1
Yield: 100.7 %

Procedure:
Sodium metal (513 mg, 22.5 mmol) was added in portions during 5 min. to a solution of 4-(3-Benzylsulfanyl-2-carboxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.9 g, 2.29 mmol) in THF (45 mL) and liquid ammonia (50 mL) at −60° C. under argon. After stirring for 15 min. ammonium chloride (1.7 g, 31.5 mmol) was added in portions. The cooling bath was removed and the ammonia was evaporated using a stream of argon. 0.5 M NaOH was added and the mixture was washed with heptane. The aqueous phase was acidified with 2 M HCl and extracted with methylene chloride. The organic phase was washed with brine, dried and concentrated under reduced pressure to give 4-(2-Carboxy-3-mercapto-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.7 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Li].O/[N:21]=[C:22](/[C:24]1[CH:41]=[CH:40][C:27]([CH2:28][N:29]2[CH2:32][CH:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]2)=[CH:26][CH:25]=1)\[NH2:23].Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[C:6]([C:16]2[O:18][N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:29]4[CH2:30][CH:31]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:32]4)=[CH:40][CH:41]=3)[N:21]=2)=[N:7][O:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CC(C)Cc1c(C(=O)O)noc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-isobutyl-5-phenylisoxazole-3-carboxylic acid, lithium salt (0.119 g, 0.472 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 0.144 g, 0.472 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.090 g, 0.472 mmol), and HOBt (0.072 g, 0.472 mmol) in N,N-dimethylformamide (3.6 mL) was stirred at room temperature for 15 min and then heated at 60° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate (2×), washed with a 10% aqueous solution of lithium chloride (2×), and dried over anhydrous sodium sulfate. The product mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a 1% mixture of methanol in dichloromethane to give tert-butyl 1-(4-(5-(4-isobutyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.179 g) as a pale yellow solid. The ester intermediate was 98% pure by HPLC with a ret. time=3.27 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=515.4.