Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:18][CH:19]=O>CCO>[N:1]1[CH:18]=[CH:19][N:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=12
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccn2ccnc2c1
Yield: 72.2 %

Procedure:
To a solution of Methyl 2-aminopyridine-4-carboxylate (10.0 g, 66 mmol, 1.0 equiv) in EtOH (150 ml) was added NaHCO3 (11.1 g, 132 mmol, 2.0 equiv) followed by chloroacetaldehyde (13.0 ml, 99 mmol, 1.5 equiv). The mixture was refluxed for 2 h. Solvents were removed under reduced pressure and the crude mixture was partitioned between water and EtOAc. The resulting precipitate was washed with Et2O and recrystallised from MeOH/Et2O to afford 8.4 g of product. 1H NMR (400 MHz, DMSO-d6): 8.66 (1H, d), 8.16 (2H, s), 7.80 (1H, s), 7.33 (1H, d), 3.90 (3H, s). MS: [M+H]+177.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:16][CH3:17])[CH3:15]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH2:16][CH3:17])[CH3:15]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.2 g) and 4-amino-1-benzyl-3-ethyl-3-methylpiperidine (0.6 g, 2.58 mmol) in methanol (210 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3-ethyl-3-methylpiperidine. Yield 0.27 g (74%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:9])=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(c1ccc(CBr)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.5 %

Procedure:
A solution of 4-(bromomethyl)benzoic acid (2.43 g, 11.3 mmol) in dichloromethane (40 ml) was treated in one portion with solid 1,1′-carbonyldiimidazole (1.83 g, 11.3 mmol). This mixture was allowed to stir at room temperature for 15 minutes. Pyrrolidine (0.8 g, 11.3 mmol) was then added and the stirring continued for 1 hour at room temperature. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and evaporated in vaccuo (i.e under reduced pressure) to give a yellow oil which was added to a 20 g pre-packed silica column and eluted from 20-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (0.5 g, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>ClC(Cl)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]3[N:14]([CH3:37])[CH:15]=[C:16]([CH2:20][C:21]4[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:33]([F:34])([F:35])[F:36]
Reactant: COc1ncc(Cc2c[nH]c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC(Cl)Cl
Product: COc1ncc(Cc2cn(C)c(CCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.8 %

Procedure:
To the solution of 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenethyl)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (308 mg, 0.596 mmol) in dichloroethane (8 mL) was added DIPEA (0.208 mL, 1.192 mmol) and MeI (0.045 mL, 0.715 mmol). The reaction mixture was stirred at room temp overnight. Concentration and purification via MDAP then provided the title compound (50 mg, 15.81% yield). LCMS: rt=3.09 min, [M+H+]=531
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1F.[NH3:11]>CO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH2:11]
Reactant: N
Reactant: Fc1cc(F)c(Cl)c(F)c1
Solvent: CO
Product: Nc1cc(F)cc(F)c1Cl
Temperature: 160 °C

Procedure:
33.4 g of 2-chloro-1,3,5-trifluorobenzene and 200 ml of methanol saturated with ammonia gas at room temperature were sealed in a Teflon-coating autoclave and heated on an oil bath at 160° C. for 40 hours. After the reaction, the solvent and unreacted 2-chloro-1,3,5-trifluorobenzene were distilled off from the reaction mixture under reduced pressure, and the remaining mixture of a solid component and an oily component was extracted with ether to obtain an oily product in an amount of 31.7 g (yield of 2-chloro-3,5-difluoroaniline: 95% determined by GLC analysis).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[C:10]([N+:23]([O-])=O)=[CH:9][N:8]=1>C1COCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[C:10]([NH2:23])=[CH:9][N:8]=1
Reactant: COc1ccc(CNc2ncc([N+](=O)[O-])c(NCc3c(F)cccc3F)n2)c(OC)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncc(N)c(NCc3c(F)cccc3F)n2)c(OC)c1
Reaction time: 16 h

Procedure:
Raney Ni was added to a solution of N2-(2,4-dimethoxybenzyl)-N4-(2,6-difluorobenzyl)-5-nitropyrimidine-2,4-diamine (0.80 g) in THF (50 mL) under argon flush. The suspension was evacuated, charged with hydrogen (balloon) and stirred for 16 hr. The resulting mixture was filtered through a celite plug that was thoroughly rinsed with THF and MeOH to yield N2-(2,4-dimethoxybenzyl)-N4-(2,6-difluorobenzyl)pyrimidine-2,4,5-triamine (54) that was used as such in the next reaction.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([NH2:18])[CH:10]=2)[CH:2]([CH3:4])[CH3:3].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[CH2:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33])=[CH:23][CH:22]=1)#[N:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:36])[CH2:29][CH:30]([CH3:35])[CH2:31][C:32]([NH:18][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=2)=[O:33])=[CH:25][CH:26]=1)#[N:20]
Reactant: CC(C)Cn1c2c(c3cc(N)ccc31)CCCC2
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.1 %

Procedure:
To a solution of the compound obtained in Step 2 (235 mg, 0.97 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (239 mg, 0.97 mmol) and DIEA (0.508 mL, 2.91 mmol) in DMF (6 mL) was added HATU (553 mg, 1.45 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (242 mg, 0.515 mmol, 53.1%) as a white powder.
Reaction SMILES: [N+:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=[O:2].[F:15]F>>[CH2:8]([O:7][C:5](=[O:6])[C:4]([F:15])([N+:1]([O-:3])=[O:2])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9]
Reactant: FF
Reactant: CCOC(=O)C(C(=O)OCC)[N+](=O)[O-]
Product: CCOC(=O)C(F)(C(=O)OCC)[N+](=O)[O-]
Yield: 76 %

Procedure:
An experiment was carried out as described in Example 2 using diethyl nitromalonate instead of diethyl malonate. Thus, 4.1 gm. (20 mmol.) diethylnitromalonate was treated with fluorine to give diethylfluoronitromalonate {δH 1.40 (6H, t, JHH 7.11, CH3), 4.47 (4H, q, JHH 7.12, CH2); δF 127.3 δC 13.7 (s, CH3), 65.2 (s, CH2), 106.3 (d, 1JCF 261.7, CF), 157.9 (d. 2JCF 25.2, CO).} in 76% yield. The conversion was 97%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:34])[CH2:30][C:31]([OH:33])=O)=[CH:24][CH:23]=1.ClC(Cl)(Cl)C#N.[NH2:41][C@@:42]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:70])([F:69])[F:68])=[CH:59][CH:58]=1)([C:53]([F:56])([F:55])[F:54])[CH2:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)=[O:45].N1C=CC=CC=1>C(Cl)Cl.CO>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:34])[CH2:30][C:31]([NH:41][C:42]([C:57]2[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH2:65][CH2:66][C:67]([F:68])([F:69])[F:70])=[CH:59][CH:58]=2)([CH2:43][C:44](=[O:45])[C:46]2[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=2)[C:53]([F:56])([F:55])[F:54])=[O:33])=[CH:26][CH:27]=1
Reactant: Cc1ccc(C(=O)C[C@](N)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Reactant: COc1ccc(NC(=O)CC(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CO
Product: COc1ccc(NC(=O)CC(=O)NC(CC(=O)c2ccc(C)cc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To triphenylphosphine (8.42 g, 32.1 mmol) in anhydrous CH2Cl2 (70 mL) was added Intermediate 6B (2.24 g, 10.7 mmol) in anhydrous CH2Cl2 (30 mL) followed by trichloroacetonitrile (1.86 g, 12.8 mmol). The mixture was stirred at rt for 3 h. The freshly prepared acid chloride was added to a solution of Intermediate 2F (1.13 g, 2.61 mmol) in anhydrous CH2Cl2 (20 mL), followed by the addition of pyridine (1.04 mL, 1.02 g, 12.85 mmol). The reaction was stirred at rt under argon overnight. The reaction was cooled to 0° C. and MeOH (40 mL) was added. The reaction was stirred at 0° C. for 10 min, then at rt for 30 min. The solvent was removed in vacuo and the crude product was purified by silica gel chromatography (120 g silica gel, eluted with EtOAc in hexanes). Product and triphenylphosphine oxide co-eluted. Fractions containing both were combined and evaporated to dryness. The solids were triturated with hexanes/EtOAc to remove most of the triphenylphosphine oxide. The product was again purified by silica gel chromatography (40 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 6C (1.03 g, 63%) as a brown oil. LCMS Anal. Calc'd for C31H30F6N2O5 624.57, found [M+H] 625.3.
Reaction SMILES: CO.[O:3]1CCO[CH:4]1[C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[C:14]1([NH:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH:4]=[O:3])=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a mixture solution of methanol and tetrahydrofuran (1:1, 20 mL) of (4-[1,3] dioxolane-2-yl-benzyl)-phenyl-amine (4.16 g, 16.3 mmol) described in Manufacturing Example 73-1-2 was added 5N hydrochloric acid (20 mL). This mixture was stirred for 1 hour at room temperature. This mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.5 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:18]([NH:20][C:21]4([C:24]([OH:26])=O)[CH2:23][CH2:22]4)=[O:19])[N:13]3[C@:12]([CH3:39])([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[C:11]2=[O:40])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].Cl.[CH3:42][N:43]1[CH:47]=[C:46]([C:48]2[CH:49]=[N:50][C:51]([C:54]3([NH2:57])[CH2:56][CH2:55]3)=[N:52][CH:53]=2)[CH:45]=[N:44]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:42][N:43]1[CH:47]=[C:46]([C:48]2[CH:53]=[N:52][C:51]([C:54]3([NH:57][C:24]([C:21]4([NH:20][C:18]([C:17]5[N:13]6[C@:12]([CH3:39])([CH2:27][C:28]7[CH:33]=[CH:32][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:30][CH:29]=7)[C:11](=[O:40])[N:10]([C:4]7[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Cl:1])[CH:3]=7)[C:14]6=[N:15][CH:16]=5)=[O:19])[CH2:23][CH2:22]4)=[O:26])[CH2:56][CH2:55]3)=[N:50][CH:49]=2)[CH:45]=[N:44]1
Reactant: C[C@@]1(Cc2ccc(OC(F)(F)F)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: Cn1cc(-c2cnc(C3(N)CC3)nc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc(C3(NC(=O)C4(NC(=O)c5cnc6n5[C@](C)(Cc5ccc(OC(F)(F)F)cc5)C(=O)N6c5cc(Cl)c(F)c(Cl)c5)CC4)CC3)nc2)cn1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 1-{[(R)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-5-(4-trifluoromethoxy-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (130 mg, 0.22 mmol) and 1-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-cyclopropylamine hydrochloride (75 mg, 0.26 mmol) in DMF (1 mL) was added diisopropylethylamine (0.15 mL, 0.87 mmol) and HATU (990 mg, 0.24). After 1 h, the reaction mixture was purified by reversed phase MPLC (C18, 30 g, Mobile phase: CH3CN (0.1% TFA), water (0.1% TFA), Gradient: 70% water to 10% water). The pure fractions were combined and concentrated in-vacuo to remove most of the CH3CN and then partitioned between 50 mL of CH2Cl2, 20 mL of water, and 10 mL of saturated aqueous NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to afford 146 mg of the title compound as a white foam, m/z=798.8.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([CH:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[OH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C[O-].[Li+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[N:44]([C:45]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:43]=[N:42][N:41]=2)=[CH:30][CH:29]=1.[I-].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:14]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[N:44]([C:45]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:43]=[N:42][N:41]=3)=[CH:32][CH:33]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:16]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[OH:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C(O)c3ccco3)ccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(C(O)c3ccco3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 154 %

Procedure:
A solution of 500 mg of 2-butyl-6-(2-furanylhydroxymethyl)-4(1H)-quinazolinone in 8 ml of N,N-dimethylformamide is stirred while 63.64 mg of lithium methoxide is added followed by 1.87 g of 5-[4'-(bromomethyl)[1,1'biphenyl]-2-yl]-1-(triphenylmethyl)-1H-tetrazole. After stirring for 10 minutes, 251.25 mg of sodium iodide is added followed by heating in an oil bath at 55° C. for 18 hours. The volatiles are evaporated in vacuo to a residue which partitioned between ethyl acetate and water. The organic layer is washed with brine, dried with anhydrous Na2SO4 and the volatiles evaporated to afford 2.0 g of a dark residue. The residue is purified by chromatography on silica gel with (2.25:1)hexanes:ethyl acetate as solvent to afford 815 mg of the desired product as a white foam. Fab Mass Spec 797 (M+Na).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([S:15][C@H:16]2[CH2:25][CH2:24][C@@H:23]3[C@@H:18]([CH2:19][C@@H:20]([C:30]([O:32]CC)=[O:31])[N:21](C(OC)=O)[CH2:22]3)[CH2:17]2)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[ClH:35]>>[ClH:35].[C:3]([C:5]1[C:6]([S:15][C@H:16]2[CH2:25][CH2:24][C@@H:23]3[C@@H:18]([CH2:19][C@@H:20]([C:30]([OH:32])=[O:31])[NH:21][CH2:22]3)[CH2:17]2)=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:4])=[O:2]
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Sc3cc4ccccc4cc3C(=O)OC)CC[C@H]2CN1C(=O)OC
Agent: Cl
Product: O=C(O)c1cc2ccccc2cc1S[C@H]1CC[C@H]2CN[C@H](C(=O)O)C[C@H]2C1
Yield: 96 %

Procedure:
The alkylated decahydroisoquinoline derivative from step C (36 mg, 0.075 mmol) was treated with 6M hydrochloric acid under reflux for 35 h. The solution was concentrated in vacuo and water added and concentrated in vacuo (3×), followed by addition of acetone and concentration in vacuo (3×), to give an off-white solid (30 mg, 96% yield).
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCOCC1.CO>[Br:23][CH2:2][C:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=1)=[O:3]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C1COc2c(cc(OCc3ccccc3)cc2C(=O)CBr)N1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
12.00 kg (40.36 mol) 8-acetyl-6-(phenylmethoxy)-2H-1,4-benzoxazin-3(4H)-one 3a are dissolved in 108 l 1,4-dioxane. Then a solution of 24.33 kg (50.45 mol) tetrabutylammonium tribromide in 48 l of 1,4-dioxane and 12 l methanol is metered into the suspension at 20° C. The reactor contents are stirred for 2 hours at 20° C. Then 72 l water are added at 20° C. within 15 minutes. After cooling to 3° C. the mixture is stirred for 1 hour, centrifuged and washed with a mixture of 9 l of 1,4-dioxane and 4.5 l water. Then it is washed with 60 l water and dried in vacuo at 50° C.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[O:21][C:20]([CH3:28])([CH3:27])[CH:19]=[C:18]2[CH:29]([CH3:31])[CH3:30])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[O:21][C:20]([CH3:28])([CH3:27])[CH:19]=[C:18]2[CH:29]([CH3:31])[CH3:30])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-6-fluoro-7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2,4,6-trienoate (Compound 108, 116 mg, 2.71 mmol) in ethanol and THF was hydrolyzed with NaOH to yield a yellow oil after purification by column chromatography (silica gel, 100% hexane to 5% to 50% ethyl acetate in hexanesethyl). The resulting oil was recrystallized from acetonitrile to produce the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:24]([N:23]([CH2:21][CH3:22])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19]C2.ClC1C=CC(C2CCNCC2)=CC=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: Clc1ccc(C2CCNCC2)cc1
Product: Clc1ccc(N2CCN(CCCc3[nH]nc4c3CCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6-tetrahydrocyclopentapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 4 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, and then by a conventional treatment using hydrochloric acid, 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-2,4,5,6-tetrahydrocyclopentapyrazole hydrochloride was obtained, m.p. 228-230° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=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>CN(C=O)C.CS(C)=O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:3]3[CH:4]=[C:5]([CH3:15])[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=4)=[CH:7][C:2]=3[F:1])=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(-c2cc(F)c(CC(=O)O)cc2C)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cc(C)c(-c4ccnc(C)c4)cc3F)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetic acid 191-6 (35 mg, 0.13 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (30 mg, 0.13 mmol) and HATU (50 mg, 0.13 mmol) in DMF (1.0 mL) was added DIEA (67 uL, 0.4 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetamide 191. MS m/z 462.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.51 (s, 1H), 8.49 (d, 1H), 8.03 (s, 1H), 7.91 (d, 1H), 7.43 (m, 1H), 7.32 (d, 1H), 7.28 (s, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 3.77 (s, 2H), 3.53 (b, 4H), 3.14 (b, 2H), 3.07 (b, 2H), 2.55 (s, 3H), 2.20 (s, 3H), 2.04 (s, 3H).