Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: N#Cc1ccc(N)cc1
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O

Procedure:
4-Aminobenzonitrile (17.58 g, 149 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absolute ethanol (450 mL). The mixture was heated at reflux overnight and the resulting suspension filtered hot to remove a small amount of a dirty yellow solid (discarded). The filtrate was gradually concentrated to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile, as a bright yellow solid, which were collected by filtration and combined. Yield: 29.11 g (81%): 1H NMR (DMSO-d6): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H), 1.46 (t, 3H).
Reaction SMILES: [C:1]([CH2:6][CH2:7][S:8]([O-:11])(=O)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(Cl)(Cl)Cl>[C:1]([CH2:6][CH2:7][S:8]([Cl:14])(=[O:11])=[O:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCS(=O)(=O)Cl
Yield: 32.2 %

Procedure:
To a stirred mixture of 90.5 g (0.44 moles) sodium 2-carboethoxyethyl sulfonate (the product of Example 26) in 300 ml chloroform, 92 g (0.44 moles) phosphorus pentachloride was added in small portions, maintaining the temperature of the reaction mixture below 40° C. during the addition. The reaction mixture was refluxed for about 6 hours, and then filtered. Nitrogen was bubbled through the solution to remove excess hydrogen chloride gas. Stripping of the solvent gave 28.4 g of the above-identified product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]2)=[C:6]([F:8])[CH:7]=1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reaction time: 16 h
Yield: 92.9 %

Procedure:
5-Amino-2-(4-methylimidazol-1-yl)fluorobenzene (50.6 g, 0.265 M) was dissolved in dry dichloromethane (800 ml) under nitrogen, and cooled to −5°. Pyridine (26.1 g, 0.33 M) was added, followed by benzyl chloroformate (49.9 g, 0.292 M) over 30 minutes. The mixture was stirred and the temperature allowed to rise to ambient over 16 hours. Aqueous sodium bicarbonate (5%, 350 ml) was added, the organic layer separated, and the aqueous layer re-extracted with dichloromethane (2×200 ml), and combined organics dried (magnesium sulfate). After filtration and evaporation, the residue was recrystallised from toluene (300 ml) to give title product (80 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30]Cl>CS(C)=O.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(NCCCCOc2ccc3ccccc3c2)cc1
Temperature: 130 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.4 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 130° C. for 7 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get as oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[4-(naphthalen-2-yloxy)butyl]amine, yellow solid, m.p 95° C., (yield 0.67 gm, 97.8%).
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C([C:16]1([CH2:26][O:27][C:28]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:31]([C:32]([OH:34])=O)=[C:30]([F:40])[CH:29]=2)[CH:23]2[CH2:24][CH:19]3CC(C[CH:17]1[CH2:18]3)[CH2:22]2)#N.C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC1CCCC2>>[C:16]12([CH2:26][O:27][C:28]3[C:36]([CH:37]4[CH2:38][CH2:39]4)=[CH:35][C:31]([C:32]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:34])=[C:30]([F:40])[CH:29]=3)[CH2:22][CH:23]1[CH2:24][CH2:19][CH2:18][CH2:17]2
Reactant: COCCS(N)(=O)=O
Reactant: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]-heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.035 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.87 (br s, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.86 (d, J=13.1 Hz, 1H), 3.72 (s, 3H), 3.36-3.31 (m, 4H), 3.22-3.19 (m, 2H), 2.12-1.96 (m, 1H), 1.95-1.67 (m, 3H), 1.66-1.50 (m, 1H), 1.44-1.04 (m, 4H), 1.02-0.82 (m, 3H), 0.76-0.55 (m, 3H), 0.43-0.30 (m, 1H); MS (ES+) m/z 426.1 (M+1)
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.CCCCCC.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[Cl-].[NH4+]>O1CCCC1>[F:15]/[C:9](=[CH:34]\[C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)/C(F)=C/c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of ethyl diethylphosphono-2-fluoroacetate (4.90 g, 20.2 mmol) in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere at 0° C. and 1.6 M n-butyllithium/hexane solution (13.1 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, and a solution of 4-nitrobenzaldehyde (3.05 g, 20.2 mmol) in tetrahydrofuran (40 mL) was added dropwise. The mixture was stirred at room temperature for 16 hr, and ice-cooled aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3%-40% ethyl acetate/hexane) to give the title compound (3.46 g, yield 72%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][NH:16]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([N:16]2[CH2:17][CH2:18][CH:19]3[CH:24]([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:15]2)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C1CCC2CNCCC2C1
Reactant: O=C(Cl)c1ccc2cccnc2c1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2cccnc2c1O)N1CCC2CCCCC2C1
Temperature: 50 °C

Procedure:
A solution of 8-hydroxyquinoline-7-carbonyl chloride of Preparation 2 (70 mg, 0.35 mmol) and decahydroisoquinoline (62.6 mg, 0.45 mmol) in THF (8 mL) and DIPEA (259 mg, 2.0 mmol) was stirred and heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM:MeOH 98:2) and then by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (49 mg, 0.16 mmol) as a off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)[N:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:28]=[N:27]1)(=[O:46])=[O:45]
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cn[nH]c5)n4n3)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(S(C)(=O)=O)c5)n4n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (1.00E2 mg, 0.267 mmol) and N,N-Diisopropylethylamine (48.8 uL, 0.280 mmol) in N,N-Dimethylformamide (12.1 mL, 156 mmol) was added Methanesulfonyl chloride (21.7 uL, 0.280 mmol). The reaction was stirred at rt overnight. LCMS 453.0 (M+H), HPLC rt=2.180 min, 97% purity. The reaction mixture was concentrated to remove DMF, diluted with CH2Cl2, and washed with sat'd aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. Product was isolated as a yellow solid (29 mg, 24%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.30 (s, 1H), 9.03 (s, 1H0, 8.97 (s, 1H), 8.71 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H0, 7.22 (dd, J=8.3 Hz, 8.3 Hz, 1H), 7.05 (bm, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.63 (dd, J=8.4 Hz, 1.4 Hz, 1H0, 3.62 (s, 3H), 3.12-3.10 (m, 4H), 2.45-2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6](/[CH:7]=[N:8]/[C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[O:28][CH3:29]>CO>[OH:15][C@H:10]1[C@H:9](/[N:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH2:14][CH2:13][N:12]([C:27]([O:28][CH3:29])=[O:30])[CH2:11]1
Reactant: COc1ccc(/C=N/[C@@H]2CCNC[C@H]2O)cc1
Reactant: COC(=O)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@@H](/N=C/c2ccc(OC)cc2)[C@H](O)C1
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of (3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (400 mg, 1.707 mmol) and DIPEA (0.447 mL, 2.56 mmol) in MeOH (50 mL) at 0° C. (ice bath) was treated with Methyl Chlorocarbonate (1 mL, 12.94 mmol). The reaction was stirred for 12 hour, and then the mixture was concentrated. The crude material was diluted with MeOH and applied on a SCX column (Phenomenex, Strata XC). The column was eluted with 2N ammonia in methanol and solvent removed to afford (3R,4R)-methyl 3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate (499 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[NH2:11])[CH:7]=[CH:8][CH:9]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[S:27]>C(Cl)Cl>[C:6]1([CH2:10][C:10]([NH:11][C:26]([NH:25][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[S:27])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:23])([F:24])[F:1])[CH:5]=2)[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: NC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)Oc1cccc(C(Cc2ccccc2)(NC(=S)Nc2cccc(C(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of bis(3-(trifluoromethoxy)phenyl)methanamine (20 mg, 0.057 mmol) in CH2Cl2 (0.1 mL) was added 1-isothiocyanato-3-(trifluoromethyl)benzene (35 mg, 0.17 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated and the residue was purified by prep HPLC (phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford 1-(2-phenyl-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(3-(trifluoromethyl)phenyl)thiourea (Example 284) as white lyophillate (30 mg, 81%). LCMS: RT=4.51 min [M+H] 645.14 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.Cl[CH2:19][C:20](=[O:22])[CH3:21]>CC(N(C)C)=O>[O:22]=[C:20]([CH3:21])[CH2:19][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)C(C)(C)N
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)NCC(C)=O
Temperature: 0 °C
Yield: 83.9 %

Procedure:
430 g (2.56 mol) of ethyl 2-aminoisobutyrate hydrochloride was dissolved in 2 l of DMAc, and 652 g (6.46 mol) of triethylamine and 373 g (4.03 mol) of chloroacetone were added thereto. The mixture was stirred and reacted under nitrogen stream at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 20 l of ice water and extracted twice with 2 l of ethyl acetate. The extracted solution was treated by a conventional method to obtain 402 g (yield: 84%) of the desired product.
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[CH:5]12[N:8]([C:9]([C:11]3[S:12][C:13]([Br:23])=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1nc(-c2ccc(Cl)cc2)c(Br)s1)N1C2CCC1COC2
Temperature: 52.5 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a stirred solution 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-(4-chlorophenyl)thiazol-2-yl)methanone (Step-2 of compound 68, 0.2 g, 0.60 mmol) in DMF (10 ml) at 0° C. was added N-bromosuccinimide (0.10 g, 0.60 mmol) in a portionwise manner. The resulting reaction mixture was stirred at 50-55° C. for 4 hrs. The progress of reaction was monitored by TLC. The reaction mixture was cooled to room temperature, water (40 ml) was added slowly and aqueous layer was extracted with ethyl acetate (2×50 ml). The organic layer was washed with water (1×30 ml). Combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.12 g, 48.6%). MS: m/z 414 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[Cl:42]C(N(C)C)=C(C)C>ClCCl>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Reactant: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21

Procedure:
The stirred solution of 0.980 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 20 ml of dichloromethane is admixed with 2.12 ml of 1-chloro-N,N,2-trimethylpropenylamine (chlorenamine) in portions over 24 hours. The reaction mixture is poured onto water (100 ml) and extracted with tert-butyl methyl ether (100 ml). The organic phase is washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.39 (2:1 EtOAc-heptane); Rt=5.57
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21]CC)=[O:20])[C:14]2=[C:13]([C:24]([O:26]CC)=[O:25])[C:12]=1[CH3:29])=[O:10].[OH-].[K+]>CO.O>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:14]2=[C:13]([C:24]([OH:26])=[O:25])[C:12]=1[CH3:29])=[O:10]
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc(SC)n2C)n2c1C(C(=O)OCC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1ccc(C(=O)c2c(C)c(C(=O)O)c3n2CCC3C(=O)O)n1C
Yield: 97 %

Procedure:
Diethyl 5-(1-methyl-5-methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (25 g) in 200 ml methanol, 50 ml H2O and 25 g KOH were heated to reflux for 8 hours. The resulting mixture was treated with 200 ml of std. NaCl and distilled to remove the methanol. The mixture was acidified with 6N HCl while stirring and then cooled. The crystalline mass obtained was separated by filtration, air dried and recrystallized from ethylacetate-ethanol to yield 21 g of 5-(1-methyl-5 -methylthio-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid, m.p. 212°-3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CN1CCCC1CCN
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine according to conditions described in general procedure C. Mp: 100-101° C., 1H NMR (400 MHz, DMSO-d6) δ 1.33-2.17 (m, 12 H), 2.88 (s, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.17-6.32 (bd, 1 H), 7.02-7.06 (m, 1 H), 7.12 (s, 1 H), 7.27 (d, J=8.7 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.61 (m, 3H), 7.82 (d, J=8.4 Hz, 1 H), 7.99 (d, J=7.7 Hz, 1 H), 8.23 (s, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9]N(CC)CC)=[CH:7][C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:5][C:4]=1[N:23]1[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]2=[N:24]1.[OH:32][C:33]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:44]=[CH:43][C:34]=1[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C[O-].[Na+]>CO>[N:24]1[N:23]([C:4]2[CH:5]=[C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:7]=[C:8]([CH2:9][C:46]3[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:44][CH:43]=[C:34]([C:35](=[O:36])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]=3[OH:32])[C:3]=2[OH:2])[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=12
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 24 h
Yield: 62 %

Procedure:
Methanol (50 ml) is placed into a 300 ml three-necked flask equipped with a stirrer, thermometer, condenser, Dean-Stark trap and nitrogen inlet. Sodium (0.3 g, 0.013 mol) is added to the methanol and the mixture stirred at room temperature till all the sodium is dissolved. Then, 2-(2-hydroxy-3-diethylaminomethyl-5-tert-octylphenyl)-2H-benzotriazole (10.2 g, 0.025 mol), 2-hydroxy-4-n-octyloxybenzophenone (8.2 g, 0.025 mol) and another 50 ml of methanol are added to the sodium methoxide solution. The reactants are heated at reflux till half the methanol is collected in the Dean-Stark trap. o-Xylene (50 ml) is added and the temperature is raised to the reflux temperature of o-xylene (143°-145° C.) and heating is continued for 24 hours. The mixture is then cooled and acetic acid is added to neutralize the sodium methoxide catalyst. The o-xylene solvent is then removed by vacuum distillation. The crude product obtained is recrystallized from heptane to afford the title compound in a yield of 10 g (62 % yield) as a white crystalline solid melting at 96°-100° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C(N(CC)CC)C>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
4-Iodobenzoyl chloride (10.0 g) was added portionwise to piperidine (3.53 g) in triethylamine (40 ml) at 0° and the suspension was stirred at room temperature under nitrogen for 1 h. The reaciton mixture was poured into 2N aqueous hydrochloric acid (200 ml) and extracted with EA (3×100 ml). The combined extracts were washed with water (100 ml), 8% aqueous sodium bicarbonate (100 ml) and water (10 ml), dried and concentrated. The resultant solid (10.25 g) was purified by FCC eluting with ER-H (1:2→1:1) to give the title compound as a white solid (9.33 g) m.p. 126°-127°.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:30]3[CH2:35][CH2:34][N:33]([CH3:41])[C@@H:32]([CH2:36][OH:37])[CH2:31]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](CO)C3)c2c1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)[C@@H](CO)C3)c2c1
Reaction time: 4 h
Yield: 85.2 %

Procedure:
The product of Example 85 (80 mg) was dissolved in dichloromethane (10 mL). Formaldehyde (0.057 mL) and sodium triacetoxyborohydride (98 mg) were then added and the mixture stirred for 4 hours. Water (10 mL) was then added and the mixture extracted with dichloromethane (30 mL). The organics were combined and evaporated under reduced pressure. The residue was purified by HPLC to give the title compound as a solid (70 mg).