Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=[O:15])[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[OH:18][C@H:10]1[C@H:9]2[CH2:17][C@H:12]([C@@H:13]([C:14]([O:16][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:15])[N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11]1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 5-6 (1.0 g) in dichloromethane (8 mL), were added benzyl alcohol (504 mg), dicyclohexylcarbodiimide (962 mg) and 4-(dimethylamino)pyridine (12 mg). The mixture was stirred at room temperature for 20 hrs.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2O[C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[OH:14].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>ClCCl>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:22]2[C:10]([CH3:13])=[N:11][N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([OH:14])[CH:4]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(O)c2)o1
Solvent: ClCCl
Product: COc1ccc(Cn2c(C)nnc2-c2ccc(C)c(O)c2)cc1
Temperature: 152.5 °C

Procedure:
A mixture of 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.65 g; 3.42 mmol) (from Example 11 supra) and 4-methoxybenzylamine (3.10 g; 22.6 mmol) (Aldrich) in a sealed reaction vessel was heated in an oil bath at 150-155° C. for 42 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane and hexanes, forcing the product to precipitate out of solution. The crude solid was collected by filtration and then precipitated again from a dichloromethane-methanol solution as the solvent was evaporated off. The solid was collected and dried, to give 5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenol. (Yield 0.849 g, 76.3%).
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)O)[CH2:3][CH2:2]1.[BrH:20].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:20][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(O)(c2cccnc2)C2CC2)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C(=CCCBr)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (470 mg) in acetic acid (5 ml) was added 48% aqueous HBr (3 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 4-bromo-1-(3-methoxyphenyl)-1-(3-pyridinyl)-1-butene (560 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([CH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=1)#[N:20]>CCO>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:21]([C:22]2[S:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=2)[C:19]#[N:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCc1nc(C(F)(F)F)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#CC(=Cc1ccc(OCc2ccccc2)cc1)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.8 %

Procedure:
NaH (516 mg, 60% dispersion in mineral oil, 12.9 mmole) was reacted with absolute EtOH (10 mL) at 0° C. After gas evolution had ceased the mixture was warmed to RT. 4-Benzyloxybenzaldehyde (2.05 g, 9.68 mmole) was added all at once as a solid. To this mixture was added dropwise a solution of 2-cyanomethyl-4(trifluoromethyl)thiazole (1.24 g) in absolute EtOH (20 mL). The reaction was stirred for 4 hr, then the solid was collected by filtration and washed with hexanes to give the title compound (1.64 g, 42% over 2 steps) as a yellow solid: 1H NMR (300 MHz. CDCl3) δ 8.25 (s, 1 H), 8.00 (d, J=6 Hz, 2 H), 7.79(s, 1 H), 7.40 (m, 5 H), 7.10(d, J=6 Hz, 2 H), 5.18 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:20][CH2:19]2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (63 mg, 0.125 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.188 mmol) to afford the crude product (75 mg) as a yellow-green solid: ESI MS m/z 568 [C31H35ClFN3O4+H]+.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:45])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([N:29]3[CH2:34][C@@H:33]([CH3:35])[N:32]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=4)[CH2:31][C@@H:30]3[CH3:44])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:16]=2)[CH2:9][CH2:8]1)C.[OH-].[Na+].Cl>C1COCC1>[F:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:32]1[C@H:33]([CH3:35])[CH2:34][N:29]([C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([CH2:6][CH2:5][C:4]([OH:46])=[O:3])[CH2:8][CH2:9]2)=[O:45])[C@@H:30]([CH3:44])[CH2:31]1
Reactant: CCOC(=O)CCN1CCCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4cccc(F)c4)C[C@@H]3C)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCC(=O)O)CC3)c2)[C@@H](C)CN1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The mixture of 3-(4-{3-[(R)-[(2S,5R)-4-(3-Fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (800 mg, Example 14), THF (10 mL) and 1 N NaOH solution (6 mL) was stirred at room temperature for overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (6 mL). The mixture was dried under rotary evaporator. For the complete removal of water, CH3OH (25 mL) was added to the flask containing the desired product and the resulting solution was dried by rotary evaporator. The process of adding CH3OH and drying CH3OH was repeated one more time. Ethanol (20 mL) was added to the residual remained in the flask. Solid (NaCl) was seen in the ethanol solution. The mixture was filtered thru a fritted filter. The solid was resined by ethanol (15 mL). The filtrate was concentrated to give crude product, which was purified by reverse phase C-18 column chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% water to 100% methanol) to give 3-(4-{3-[(R)-[(2S,5R)-4-(3-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid (320 mg; 42%). 1H NMR (300 MHz, CD3OD) δ 7.61 (m, 1H), 7.50-7.39 (m, 2H), 7.32 (m, 2H), 7.20-7.08 (m, 3H), 6.98 (m, 1H), 6.73 (m, 3H), 5.16 (s, 1H), 3.99-3.92 (m, 2H), 3.60 (bs, 1H), 3.50 (m, 2H), 3.35 (m, 2H), 3.23 (m, 3H), 3.08 (m, 1H), 2.99 (m, 1H), 2.75-2.66 (m, 4H), 2.54 (m, 1H), 2.46 (m, 1H), 2.17-1.99 (m, 4H), 1.13 (m, 6H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:12][CH2:13][CH2:14][O:15]1)[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 180 g) in ethanol (1080 ml) was added 1N aqueous solution of sodium hydroxide (1660 ml) and the mixture was stirred for 2 hours and 10 minutes at ambient temperature. After the reaction mixture was adjusted to pH 7.3 with 6N hydrochloric acid, ethanol was distilled off under reduced pressure and then washed with diethyl ether (500 ml×2). To the resultant was added diethyl ether (1 l), adjusted to pH 1.5 with 6N hydrochloric acid and then diethyl ether layer was separated. The remaining aqueous layer was further extracted with diethyl ether (350 ml), and the remaining aqueous layer was adjusted to pH 1.3 with 6N hydrochloric acid and then further extracted with diethyl ether (350 ml×2). The diethyl ether layer and extracts were combined together, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was concentrated to give an oil (155.6 g) of 2-methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer). (Yield: 99.3%)
Reaction SMILES: [CH3:1][N:2]([C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:32]([OH:39])[CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]([CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:14][CH2:15]2)[S:8][CH:9]=1)=[O:4]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CC[C@H](O)c4ccccc43)cs2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3CCC(=O)c4ccccc43)cs2)CC1

Procedure:
A mixture of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R,4S)-1,2,3,4-tetrahydro-4-hydroxy-1-naphthalenyl]-4-thiazolecarboxamide and its enantiomer (96 mg, 0.17 mmol) (i.e. the product of Example 26, Step B) and manganese dioxide (400 mg, 4.6 mmol) in chloroform (2 mL) were swirled to form a vortex overnight at room temperature. The reaction mixture was filtered through Celite® diatomaceous filter aid, and purified by medium-pressure liquid chromatography on silica gel using 20% acetone in ethyl acetate as eluant to give 70 mg of the title compound, a compound of the present invention as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:1][C:2]1[CH:9]=[C:8]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NCC1CCOCC1
Reactant: N#Cc1cnc(N)cc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(N)cc1NCC1CCOCC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (84 mg, 0.729 mmol) were dissolved in NMP (1 ml) and treated at room temperature with DIPEA (0.219 ml, 1.09 mmol). The reaction mixture was then stirred at 50° C. for 4 h and at 90° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with water and diluted with EtOAc. The layers were separated and organic layer was washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as an off-white solid. (UPLC-MS 3) tR 0.40 min; ESI-MS 233.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.Cl.[NH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCCC1.O>[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1)=[O:28]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)ccc21
Reactant: CC(C)(N)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)C(C)(C)N)ccc21
Reaction time: 0.25 h

Procedure:
8 g (0.026 mol) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one are stirred at room temperature for 1 hour with 5 g of α-aminoisobutyric acid chloride hydrochloride in 30 ml of tetrahydrofuran, 8 g of potassium carbonate are subsequently added thereto and, after a further 15 minutes, the mixture is treated with methylene chloride and water. The organic phase is separated and the aqueous phase is extracted four times with methylene chloride. The combined organic extracts are dried and evaporated. The residue is purified on 350 g of silica gel with methylene chloride/ethyl acetate (1:1) and ethyl acetate as the elution agent. From ethyl acetate/ether there is obtained 2-amino-N-[5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-2-methylpropionamide of melting point 250°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[N:3][C:4]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:5]2
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OB(O)c1ccccc1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3)c2cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and Phenylboronic acid to give (6,7-dimethoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([O:12][CH3:13])[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH3:13][O:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Temperature: 100 °C

Procedure:
In a sealed tube, a mixture of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (4.22 g, 17.2 mmol) and triethyl phosphite (3.5 g, 21 mmol) was heated to 100° C. for 16 h. The reaction was cooled to ambient temperature, transferred to a round bottom flask, and concentrated in vacuo. The crude oil was adsorbed onto a pre-filled solid loading cartridge [RediSepRf 25 gram] and purified using the Teledyne/ISCO system [RediSepRf Silica 40 gram], eluting with 0-5% MeOH:CH2Cl2. The desired fractions were combined and concentrated in vacuo, affording the title material as a yellow oil, 5.0439 g (87%, 14.970 mmol). 1H NMR (CDCl3) δ ppm 7.83 (dd, J=8.2, 0.9 Hz, 1H), 7.08 (t, J=1.9 Hz, 1H), 6.94 (dt, J=8.3, 2.0 Hz, 1H), 4.07 (ddd, J=8.3, 7.1, 1.3 Hz, 4H), 3.97 (s, 3H), 3.14-3.25 (m, 2H), 1.29 (t, J=7.1 Hz, 6H). MS (ES+): m/z 304.00 (100) [MH+]. HPLC: tR=2.89 min (ZQ3, polar—5 min).
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([CH:16]=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:5].[CH:20]1([Mg]Cl)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)C>[CH:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]1[CH2:7][C@@H:6]([C:4]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:5])[CH2:18][CH2:17][N:9]12
Reactant: Cl[Mg]C1CCCC1
Reactant: CON(C)C(=O)[C@H]1CCn2c(cc3ccccc32)C1
Solvent: CCOCC
Product: O=C(C1CCCC1)[C@H]1CCn2c(cc3ccccc32)C1

Procedure:
In a manner analogous to that described in Example 11(iii), from 2.0 g (7.75 mmol) of 6,7,8,9-tetrahydro-N-methoxy-N-methylpyrido[1,2-a]indole-8(S)-carboxamide and 15 ml (30 mmol) of a 2M solution of cyclopentylmagnesium chloride in diethyl ether, there were obtained 1.1 g of cyclopentyl 6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl ketone as a pale yellow solid of melting point 69° C.
Reaction SMILES: C(SCC(NCCC(O)=O)=O)(=O)C.O[C:15](C)([C:21]([OH:23])=[O:22])[C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17].C(N(CC)CC)C>CN(C)C=O>[NH2:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][C:21]([OH:23])=[O:22]
Reactant: CC(O)(C(=O)O)[C@H](N)C(=O)O
Agent: CC(=O)SCC(=O)NCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
Compound 8 (1.0 g; 3.07 mmoles) was dissolved in dimethylformamide (7 ml). β-Hydroxy,β-methyl-aspartic acid (0.5 g; 3.07 mmoles) was added to the solution. Triethylamine (0.64 ml; 4.5 mmoles) was added to the stirred suspension. Stirring was continued for 2.5 hours, after which a clear solution was obtained. The solvent was then evaporated in vacuo. The residue was dissolved in water and the aqueous solution was subsequently extracted three times with ethyl acetate in order to remove the p-nitrophenol. Following acidification of the aqueous solution to pH 1-2 by addition of 5% (w/w) aqueous potassium bisulfate, the solution was extracted four times with dichloromethane-butanol-2 (3:2; v/v). The combined organic extracts were evaporated in vacuo to give compound 9 as a syrup. The product was purified by column chromatography on silica(R) ("Merck" 40-63 μm) using butanol-1-acetic acid-water (4:1:1; v/v) as the eluent. Fractions containing pure 9 were combined and evaporated in vacuo. The residue was dissolved in water upon which the product was isolated by lyophilization (450 mg; 42%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13][CH3:14])=[O:12])(=[O:4])=[O:3].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:5]([C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:11]([O:13][CH3:14])=[O:12])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:20][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1sccc1NS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1sccc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 3-(methylsulfonamido)thiophene-2-carboxylate (prepared in an analogous manner as described in Example 8, Scheme 8, Step 1, 500 mg, 2.125 mmol), 4-(2-chloroethyl)morpholine hydrochloride (435 mg, 2.338 mmol) and potassium carbonate (646 mg, 4.68 mmol) in dry DMF (13 ml) was heated at 80° C. for 5 h and stirred at RT for 3 days. The solvent was evaporated, the residue was diluted with EtOAc and washed with H2O and brine; the organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/EtOAc=8/2 to 7/3 and then DCM/MeOH=95/5) to afford methyl 3-(N-(2-morpholinoethyl)-methylsulfonamido)thiophene-2-carboxylate (Int. 50) (655 mg, 1.880 mmol, MS/ESI+ 348.9 [MH]+).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.CC1(C)[O:33][C@@H:32]([CH:34]=O)[CH2:31][O:30]1.Cl.CO.Cl>>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:34][C@H:32]([OH:33])[CH2:31][OH:30])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: CC1(C)OC[C@H](C=O)O1
Agent: Br
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NC[C@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde. The protecting group is cleaved off as described by means of a 1.25 N HCl/methanol solution. The product was converted into the hydrochloride.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:47][CH2:48][CH2:49][CH3:50])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)c1cccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and propylamine (8.2 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (15 mg, 53%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:15][C:16]([OH:18])=[O:17]
Reactant: COc1ccccc1CCO
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1CCOCC(=O)O
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
The solution of 10.0 g of 2-(2-methoxyphenyl)ethanol in 130 ml of dimethyl sulphoxide is admixed with stirring with sodium hydride dispersion (60%) and stirred at 60° C. over 10 min. The suspension is admixed slowly with 6.20 g of chloroacetic acid and subsequently stirred at 80° C. over 2 hours. The reaction mixture is cooled, poured onto ice-water (0.5 l) and washed with ethyl acetate (1×250 ml). The aqueous phase is acidified with 2M HCl and extracted with ethyl acetate (2×250 ml). The organic phases are washed successively with water (250 ml) and brine (1×250 ml), dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.04 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=3.44.