Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[Cl:23][C:24]1[CH:25]=[C:26]([N+:31]([O-:33])=[O:32])[CH:27]=[CH:28][C:29]=1Cl>CN(C=O)C>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][C:29]2[CH:28]=[CH:27][C:26]([N+:31]([O-:33])=[O:32])=[CH:25][C:24]=2[Cl:23])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Sc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.2 mL, 7.8 mmol) was added dropwise to a solution of 4-tert-butylthiophenol (0.95 g, 5.7 mmol), 3,4-dichloronitrobenzene (1.0 g, 5.2 mmol), and DMF (15 mL). The solution was stirred for 1 h at ambient temperature then 1 h at 60° C. The mixture was allowed to cool and was poured over ice. The resulting yellow precipitate was collected and dried. The crude product was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:21]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:29]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:27][C:22]3([CH2:23][CH2:24][CH2:25][CH2:26]3)[C:21]=2/[CH:8]=[CH:9]/[CH:10]=[O:11])=[CH:16][CH:15]=1
Reactant: Fc1ccc(C2=CC3(CCCC3)CC(c3ccc(F)cc3)=C2)cc1
Reactant: CN(C)C=CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: O=C/C=C/C1=C(c2ccc(F)cc2)C=C(c2ccc(F)cc2)CC12CCCC2
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a solution of phosphorus oxychloride (1.69 ml, 18.15 mmoles) in 50 ml of acetonitrile cooled in an ice bath was added 3-dimethylaminoacrolein (1.68 ml, 16.75 mmoles) dropwise over 3 minutes. The mixture was stirred for 5 minutes and a solution of 7.9-di-(4-fluorophenyl)-spiro[4.5]-deca-6,8-diene (4.5 g, 13.96 mmoles) in 150 ml of warm acetonitrile was added dropwise over 30 minutes. The mixture was stirred at room temperature for 16 hours and was then heated in an oil bath at 60° C. for 6 hours. The mixture was cooled and poured into 400 ml of cold 1N sodium hydroxide. The mixture was extracted with ether. The ether was washed with water and evaporated in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][Br:13])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 70 %

Procedure:
A solution of 4-methyl-2-nitroanisole (25 mmol), N-bromosuccinimide (25 mmol) and benzoyl peroxide (2.5 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 18 h. The heated mixture was then poured into water. A solid precipitate formed and was separated by filtration. The aqueous filtrate was extracted with carbon tetrachloride (3×50 mL). The extract was concentrated under reduced pressure to yield a solid product. The solid products (the filtered precipitate and product of evaporating the extract) were combined and recrystallized from ethyl acetate-hexane to yield 4-methoxy-3-nitro benzyl bromide as a crystalline product in 70-75% yield. m.p. 110-112° C.
Reaction SMILES: C([Sn]1(CCCC)[O:10][CH2:9][C:8]2([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:7][O:6]1)CCC.[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25](=S)[O:24][CH2:23]1)[CH3:21]>>[CH2:20]([C:22]1([CH2:29][CH3:30])[CH2:27][O:26][C:25]2([O:6][CH2:7][C:8]3([CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]3)[CH2:9][O:10]2)[O:24][CH2:23]1)[CH3:21]
Reactant: CCC1(CC)COC(=S)OC1
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CCC2)CO1
Product: CCC1(CC)COC2(OC1)OCC1(CC=CCC1)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To the above solution of 3,3-dibutyl-2,4-dioxa-3-stannaspiro[5.5]undec-8-ene 2 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.39 g, 59.6 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 3,3-diethyl-1,5,7,16-tetraoxadispiro[5.2.5.2]hexadec-11-ene (DECH 3) was obtained as colorless oil in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ 5.68-5.58 (m, 2H), 3.74-3.68 (4s, 8H), 2.08-1.94 (m, 4H), 1.63-1.56 (t, 2H, J=6.6 Hz), 1.46-1.37 (q, 4H, J=7.5 Hz), 0.84-0.76 (t, 6H, J=7.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 126.03, 124.16, 114.68, 70.03, 69.32, 34.27, 30.50, 26.44, 23.14, 21.30, 13.92, 7.01; IR (neat) (cm−1) 3020, 2960, 2880, 1640, 1450, 1360, 1250, 1220, 1200, 1185, 1160, 1105, 1020, 995, 920, 730, 655; Anal. Calcd for C16H26O4: C, 68.06%; H, 9.28%; Found: C, 68.20%; H, 9.59%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][CH2:3][C@@H:2]([NH:1][S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:11]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)C[C@H](N)CN2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a suspension of 1F (103.9 mg, 0.6 mmol) in CH3CN (3 mL) at RT under argon was added DIPEA (0.11 mL, 0.66 mmol), followed by dropwise addition of benzene sulfonylchloride (0.08 mL, 0.63 mmol). The reaction mixture was stirred at RT for 1.5 h, then concentrated under reduced pressure. The residue was taken into EtOAc, washed with water, brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (30-50%) in hexane to give the title compound (170 mg, 90%). HPLC: 99% at 5.2 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 314 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: COc1nn(C)c(=O)n1-c1ccsc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1nn(C)c(=O)n1-c1ccsc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
To a suspension of the title compound of Step E (2.6 g) in methylene chloride (20 mL) under N2 at room temperature was added sequentially triphenylphosphine (3.44 g) and carbon tetrabromide (5.58 g). The resulting orange solution was allowed to stir for 1 h at room temperature and was then concentrated under reduced pressure to give an orange oil. The residue was purified by flash chromatography (1:1 ethyl acetate:hexane as eluent) to afford 2.3 g of the title compound of Step F, a compound of the invention, as a white solid. 1H NMR (CDCl3): δ 7.34 (d,1H), 6.92 (d,1H), 4.65 (s,2H), 3.98 (s,3H), 3.45 (s,3H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:18][C:19]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:28]2[CH:27]=[N:26][C:25]([N:22]3[CH2:23][CH2:24][C:19]([CH3:18])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:20][CH2:21]3)=[N:30][CH:29]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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+]
Solvent: C1COCCO1
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
To a solution of Intermediate 3 (22.7 g, 53.2 mmol) and iv (20 g, 53.2 mmol) in 1,4-dioxane:MeOH (300:180 mL) was added potassium phosphate (17 g, 79 mmol) at RT. The resulting mixture was degassed for 15-20 min by purging N2 followed by the addition of Pd(PPh3)4 (6.1 g, 5.32 mmol). The reaction mixture was again degassed for another 15-20 min and then heated up to 80° C. for 5 h. The reaction mixture was cooled to RT, diluted with EtOAc (500 mL) and passed through celite bed. The filtrate was evaporated and the crude residue was purified by chromatography on silica eluting with 1.5% MeOH:DCM to obtain Intermediate 7 (12 g, 41%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([O:21]CC)=O)=[CH:17][N:18]=3)[CH:15]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C[NH:58][C:59]1[CH:64]=[C:63]([C:65]2[N:69]=[C:68]([CH:70]3[CH2:73][C:72]([F:75])([F:74])[CH2:71]3)[O:67][N:66]=2)[CH:62]=[CH:61][C:60]=1[CH3:76]>CN1C(=O)CCC1>[F:75][C:72]1([F:74])[CH2:71][CH:70]([C:68]2[O:67][N:66]=[C:65]([C:63]3[CH:62]=[CH:61][C:60]([CH3:76])=[C:59]([NH:58][C:19]([C:16]4[N:14]5[CH:15]=[C:10]([CH2:9][CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)[CH:11]=[CH:12][C:13]5=[N:18][CH:17]=4)=[O:21])[CH:64]=3)[N:69]=2)[CH2:73]1
Reactant: CNc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1C
Reactant: CCOC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of ethyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (114) (25 mg, 0.087 mmol) in anhydrous NMP (1 mL) was added HATU (26 mg, 0.104 mmol) and DIEA (23 uL, 0.130 mmol). The reaction mixture was stirred at room temperature for 10 minutes. Then, 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (37) (23 mg, 0.087 mmol) was added and the reaction was stirred for two days. The crude product was purified by reverse phase preparative HPLC to afford N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxamide (F63). MS m/z 536.3 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:31])[CH2:9][CH2:8][N:7]([C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CN(C)C=O>[F:31][C:4]1([F:3])[CH2:9][CH2:8][N:7]([C:10]([C:12]2[N:13]([S:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)(=[O:41])=[O:40])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:29])[CH3:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 24 mg, 1.1 eq.) was added to a mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 200 mg, 1.0 eq.) in N,N-dimethylformamide (2 mL) and stirred at 70° C. for 30 min. 4-Fluorobenzenesulfonyl chloride (115 mg, 1.2 eq.) was added and the reaction mixture was stirred at 70° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, evaporated to dryness and purified on silica gel, eluting with dichloromethane/methanol 49:1 to yield 167 mg (60%) of the desired product as yellow foam. MS (m/e): 564.4 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Br.[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][N:31]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:30]2)(=[O:24])[CH3:23]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 56.4 %

Procedure:
422 mg of 9,10-difluoro-2,3-dihydro-3methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 382 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7]
Reactant: CNOC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a stirred solution of 3-(dimethylamino)benzoic acid (16.5 g, 100 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.39 mL, 5 mmol) followed by oxalyl chloride (10.5 mL, 120 mmol). The resulting mixture was stirred 4 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (13.7 g, 140 mmol) was added at once, followed by dropwise addition of triethylamine (55.8 mL, 400 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, then washed with brine. The aqueous layers were extracted with dichloromethane (2×50 mL), then the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 3-(dimethylamino)-N-methoxy-N-methylbenzamide as an oil [15.5 g, yield 67%; HPLC/MS:m/z=209 (M+H); log P(HCOOH)=0.95].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.[CH:14]([NH:16][NH:17][CH:18]=O)=O>>[N:16]1[N:17]=[CH:18][N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]3)[CH:14]=1
Reactant: Cc1cc(N)cc2ccc(=O)[nH]c12
Reactant: O=CNNC=O
Product: Cc1cc(-n2cnnc2)cc2ccc(=O)[nH]c12

Procedure:
A mixture of 6-amino-8-methyl-2-(1H)-quinolone (0.485 g) and 1,2-diformylhydrazine (0.245 g) was stirred and heated in a melt at 200° for 1 hour. The residue was then triturated with hot isopropanol, cooled and filtered and the solid residue was recrystallised from chloroform-isopropanol to afford 6-(1,2,4-triazol-4-yl)-8-methyl-2-(1H)-quinolone 0.25 H2O, m.p. 369°-371° (0.112 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17])#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:17])#[N:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
1,2,3,4-tetrahydroquinoline (4.2 g, 31 mmol) was added dropwise to a solution of 3-cyanobenzoyl chloride (5.2 g, 31 mmol) and triethylamine (3.1 g, 31 mmol) in dichloromethane (125 ml) while cooling in an ice/water bath. The mixture was allowed to warm to RT and stirred for 18 h. It was washed with 0.3M potassium hydrogen sulphate solution, saturated sodium hydrogen carbonate solution and brine. The organic phase was filtered through phase separation paper and reduced to yield 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7.1 g, 86%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: NC1CC1
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC2CC2)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
Cyclopropylamine (249 μL, 3.59 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (190 mg, 0.512 mmol) in tetrahydrofuran (6 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Cyclopropylamine (71.0 μL, 0.102 mmol), sodium cyanoborohydride (97.0 mg, 1.54 mmol) and acetic acid (293 μL, 5.12 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine, and dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 34 mg of the cis isomer of the title compound (16%) as a pale yellow oily substance and 32 mg of the trans isomer of the title compound (15%) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13])[CH3:2].[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([N:11]=[C:18]=[O:17])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13])[CH3:16]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)C(=O)c1cc(N)c(F)cc1Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1cc(N=C=O)c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
13.5 g of of N,N-diethyl-5-amino-2-chloro-4-fluorobenzamide in 150 ml of ethyl acetate are added dropwise while stirring within 30 minutes to a solution, heated to 70° C., of 6.7 ml of diphosgene in 50 ml of ethyl acetate. The reaction mixture is then heated at reflux temperature for 2 hours. Subsequently, the solvent is distilled off at normal pressure and the residue is distilled in a bulb-tube. There is obtained N,N-diethyl-2-chloro-4-fluoro-5-isocyanatobenzamide, b.p. 170° C./0.06 mmHg; nD 1.542, used as the starting material in Example 3.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:12](=[O:14])[CH:2]3[CH2:3][CH:4]([CH:5]4[CH2:6][CH2:7][CH2:8][CH:1]43)[C:9]2=[O:11])[CH2:28][CH2:29]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C(O)C1CC(C(=O)O)C2CCCC12
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CCCC21

Procedure:
Bicyclo[3.3.0]-octane-2,4-dicarboxylic acid (1.6 g., 8.1 mmole) was converted to the anhydride by refluxing for three hours in 100 ml. of acetic anhydride. The excess reagent was removed in vacuo. Two hundred fifty (250) ml. of xylene was added along with 1.9 g. (8.1 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine. The mixture was refluxed under nitrogen for 48 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuo and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. Removal of solvent and recrystallization of the residue from isopropanol with the addition of 4N isopropanolic HCl, followed by a second recrystallization from isopropanol, gave 750 mg. of white solid title compound as hydrochloride, one quarter hydrate, m.p. 188°-189° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[F:38][C:39]1[CH:40]=[C:41]([OH:46])[CH:42]=[CH:43][C:44]=1[F:45]>>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[F:45])[O:46][C:5]1[N:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1ccc(F)c(F)c1
Agent: [Li]CCCC
Product: Fc1ccc(Oc2nc(OC3CCCCC3)c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(cyclohexyloxy)-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (Lower Rf product) (Example 52, Step A), (26 mg, 0.05 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3,4-difluorophenol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 95/5 hexanes/ethyl acetate) afforded title compound. HPLC/MS: m/e=563 (M++1); Rt=5.25 min. 1H-NMR 500 MHz (CDCl3): 1.28-1.40 (m, 4H), 1.55 (m, 3H), 1.65 (m, 2H), 1.90 (m, 2H), 5.03 (m, J=4 Hz, 1H), 7.05 (m, 4H), 7.10 (m, 5H), 7.34 (d, J=2 Hz, 1H).