Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:35]5[C@H:34]([CH3:33])[CH2:38][O:37][C:36]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2N2CCCS2(=O)=O)CC1
Yield: 84.4 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (519 mg) described in Preparation Example 179 and (R)-4-methyloxazolidin-2-one (121 mg) described in Preparation Example 25, the title compound (455 mg) was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.CO.[ClH:11]>O1CCCC1>[ClH:11].[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1
Reactant: N#CCc1ccsc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Slowly add borane methyl sulfide complex (30.4 mL, 304.4 mmol) to a solution of thiophen-3-yl-acetonitrile (25.0 g, 203.0 mmol) in tetrahydrofuran (450 mL). Heat the reaction at reflux for 16 h and then cool to RT. Slowly quench the reaction with methanol (50 mL) until no foaming is observed. To this mixture slowly add methanol (100 mL) which is saturated with hydrogen chloride. Stir the mixture at RT for 20 min before concentrating in vacuo. Add methanol (100 mL) to the mixture and concentrate in vacuo. Suspend the resulting solid in diethyl ether (200 mL) and filter to afford 31.1 g (94%) of the crude title compound. MS/ES m/z 128.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])[O:4][CH2:3]1.[Na+].[CH3:21][S:22]([O-:24])=[O:23]>CN(C)C=O>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:14][CH:13]=2)=[O:11])[O:4][CH2:3]1
Reactant: CC1(C)COC(CCC(=O)c2ccc(F)cc2)OC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC(CCC(=O)c2ccc(S(C)(=O)=O)cc2)OC1
Temperature: 75 °C
Yield: 78.8 %

Procedure:
To a solution of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one (Step 4) (1.68 g, 6.3 mmol) in dimethylformamide (75 ml), methanesulfinic acid sodium salt (2.9 g, 28.4 mmol) was added. The reaction mixture was heated at 120-30° C. for 72 hours. After cooling, the solvent was removed under reduced pressure and the reaction mixture was diluted with water. The material was extracted with methylene chloride and washed with brine. After drying (MgSO4), filtration and concentration, the crude solid (2.78 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give the sulfone (1.62 g, 79%) as a white solid: mp (DSC) 104° C. Anal Calc'd. for C16H22SO5 : C, 58.88; H, 6.79; S, 9.82. Found: C, 58.76; H, 7.01; S, 10.21.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][CH:4]2[C:3]1=[O:13].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>ClCCCl>[C:21]([O:1][N:2]1[C:6](=[O:7])[CH:5]2[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][CH:4]2[C:3]1=[O:13])(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CC1CCC2C(=O)N(O)C(=O)C2C1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=CC(=O)ON1C(=O)C2CCC(C)CC2C1=O
Temperature: 25 °C
Yield: 90.4 %

Procedure:
Next, 10.07 g (0.055 mol) of N-hydroxy-4-methylhexahydrophthalimide, 15 ml (0.11 mol) of triethylamine, and 50 ml of 1,2-dichloroethane were poured in a 100 ml flask. Then, 7.2 ml (0.090 mol) of acrylyl chloride was slowly dropped therein at a room temperature under nitrogen with stirring. After the dropping, a mixture thus prepared was reacted for one hour at a room temperature. A reaction mixture was washed with water so as to separate an organic layer therefrom. Then, the organic layer was washed with a 5% sodium hydrogen carbonate aqueous solution. The organic layer separated from the 5% sodium hydrogen carbonate aqueous solution was dried with magnesium sulfate, and then a solvent was removed from the organic layer. 11.8 g of N-(acryloyloxy)-4-methylhexahydrophthalimide (viscous liquid of dark yellow color) was thereby obtained. N-(acryloyloxy)-4-methylhexahydrophthalimide is represented by the following formula (120):
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Product: CCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.107 g, 0.387 mmol) was reacted with N-(2-azidoethyl)dodecanamide (0.104 g, 0.387 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-dodecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), δ 6.94 (s, 1H), δ 6.49 (s, 1H), δ 6.23 (s, 2H), δ 4.46 (t, 2H), δ 3.74 (q, 2H), δ 2.68 (t, 2H0, δ 2.34 (t, 2H), δ 2.16 (t, 2H), δ 1.54 (m, 13H), δ 1.47 (m, 2H), δ 1.24 (m, 18H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.3, 150.4, 149.5, 148.3, 138.5, 121.9, 106.5, 84.9, 49.5, 39.5, 36.6, 34.1, 32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 29.3, 28.9, 28.2, 28.1, 29.0, 26.9. 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C29H51N7O3 (M+) 545.4053. found 545.4053, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)dodecanamide hydrochloride (0.155 g, 83% yield). 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), δ 6.49 (s, 1H), δ 4.63 (s, 2H), δ 3.97 (s, 2H), δ 2.81 (s, 2H), δ 2.51 (t, 2H), δ 2.51 (t, 2H), δ 2.14 (t, 2H), δ 1.76 (s, 2H), δ 1.67 (s, 2H), δ 1.51 (s, 2H), δ 1.44 (s, 2H), δ 1.26 (bs, 16H), δ 0.71 (s, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 159.4, 147.3, 127.6, 108.5, 51.3, 48.6, 38.8, 35.8, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 28.2, 28.1, 27.7, 24.8, 24.2, 23.9, 22.6, 22.5, 13.4, 13.3 ppm; HRMS (ESI) calcd for C24H43N7O (M+) 445.3429. found 445.3524.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16](C4C=CC(F)=CC=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])C[CH2:2]1.C(NC(C1NC=C(C(C2C([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=3)=NOC=2C)=O)C=1)=O)C#C>>[CH2:4]([NH:5][C:6]([C:8]1[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]2[C:16]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=3)=[N:17][O:18][C:19]=2[CH3:20])=[O:14])[CH:12]=1)=[O:7])[C:1]#[CH:2]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Reactant: C#CCNC(=O)c1cc(C(=O)c2c(-c3cccc(F)c3)noc2C)c[nH]1
Product: C#CCNC(=O)c1cc(C(=O)c2c(-c3cccc(F)c3)noc2C)cn1C
Yield: 43 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid prop-2-ynylamide (example 179) in 43% yield as white solid. (m/e): 366.1 (M+1; 100%).
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[NH2:12]OS(O)(=O)=O>O>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:12])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(F)c(Br)cc1F
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1cc(F)c(Br)cc1F
Yield: 66.3 %

Procedure:
4-Bromo-2,5-difluorobenzaldehyde (1.82 g, 8.3 mmol) and hydroxylamine-O-sulphonic acid (1.1 eq., 1.03 g) in water (40 ml) were heated to 100° C. for 6 h, cooled and extracted with ethyl acetate. The organic layer was dried (sodium sulphate) and evaporated to give the title compound as a pale yellow solid (1.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH:29]=1>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)=[O:16])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccccc2C(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCCCOc2ccccc2C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O
Yield: 65 %

Procedure:
The reaction of 0.79 g of 2-[3-(4-acetyl-3hydroxy- 2-propylphenoxy)propoxy]benzoic acid with 0.35 g of 3-pyridine butanamine according to Example 40 gave 0.70 g, mp 104°-107°, (65% yield) of 2-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9](=[O:10])[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CI
Reactant: O=C(Cc1ccc(Cl)cc1)N1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)N1CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
16.8 g (0.075 mol) of 2-(4-chlorophenyl)-1-(pyrrolidin-1-yl)-ethanone are dissolved in 175 ml dimethylsulphoxide and after the addition of 8.9 g (0.08 mol) of potassium tert.butoxide, stirred for 15 minutes at ambient temperature. After the addition of 18.1 ml (0.085 mol) of ethyl iodoacetate the reaction mixture is stirred for 45 hours at ambient temperature. The solution is poured onto ice water and extracted with ethyl acetate. The combined organic extracts are washed with sodium chloride solution, dried and evaporated down. The residue is chromatographed on silica gel, eluting first with petroleum ether and later with petroleum ether/ethyl acetate (8:2 and 1:1). The desired fractions are combined and evaporated down.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO[CH:13]=[CH:14][C:15](=[O:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:4]1([C:3]2[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC=CC(C)=O
Reactant: O/N=C(\Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1conc1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a mixture of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (7.41 g, 48 mmol) and 4-methoxy-3-buten-2-one (4.77 mL, 48 mmol) in dichloromethane (48 mL) was added triethylamine (6.64 mL, 48 mmol) dropwise under ice-bath cooling keeping the temperature below 5° C. The reaction mixture was then stirred at 5° C. for 15 min, and then the ice-bath was removed and stirring was continued for 30 min (resulting in an increase in temperature to 32° C. Then the mixture was re-cooled under ice-bath cooling for another 30 min and then the ice-bath was removed again and allowed to warm up to room temperature and left overnight. The resulting mixture was then poured into HCl (1 N) and ice-water and then extracted with ethyl acetate. The organic extract was then dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (6.35 g, 71%) which was obtained as a light yellow solid. MS: m/e (EI)=187.1 [M].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][Mg]Br)[CH3:10]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:9]([CH:11]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:11]([CH2:9][CH3:10])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:10]
Reactant: Clc1ccccc1Cl
Reactant: CCCCC(CC)C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCCCC(CC)Cc1ccccc1CC(CC)CCCC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A dry 2 L 3-neck flask with attached reflux condenser and addition funnel, flushed with dry nitrogen, was charged with 1,2-dichlorobenzene (79.4 g, 540 mmol), Ni(dppp)Cl2 (3 g, 6 mmol), and 200 mL of dry Et2O. The addition funnel was charged with 2-ethylhexylmagnesium bromide (3M, 400 mL). The solution was cooled to 5° C. and the Grignard reagent was added dropwise to the reaction. After complete addition, the reaction was stirred at 5° C. for 30 min and then warmed to room temperature (RT). The reaction was then heated to reflux for 12 h. After cooling to RT, the reaction mixture was poured onto an ice/HCl (10%) solution and extracted with MTBE. The organic fractions were dried over anhydrous MgSO4 and then concentrated. The product was purified first by distillation followed by column chromatography with hexanes, and isolated as colorless oil (101 g, 62%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C(N(CC)C(C)C)(C)C.Cl[C:17]([O:19][CH:20]([Cl:22])[CH3:21])=[O:18]>O1CCCC1>[Cl:22][CH:20]([O:19][C:17]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH3:21]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COC(=O)CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COC(=O)OC(C)Cl
Reaction time: 3 h

Procedure:
To an ice-water bath cooled solution of methyl glycolate (13.5 mL) and N,N-diisopropylethylamine (30.46 mL) in tetrahydrofuran (180 mL) was added dropwise with stirring 25.0 g of 1-chloroethyl chloroformate. The 0° C. bath was removed, and the mixture stirred for an additional 3 hr. After filtration to remove insoluble amine hydrochloride, the THF solution was evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, dried over anh. sodium sulfate, and evaporated under reduced pressure to give 31.1 g of reddish oil. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-].Cl>CN(C=O)C>[C:17]([O:21][C:22]([CH2:23][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[C:7]([C:12]([OH:14])=[O:13])=[CH:8]1)=[O:25])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)O)cn(CC(=O)OC(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled suspension of 6-methoxy-1H-indole-3-carboxylic acid (1 g, 5.23 mmol) in DMF (35 mL) was added NaH (60% suspension in oil; 0.523 g, 13.1 mmol) in one portion, and the mixture was stirred at 0° C. for 30 min. Tert-butyl-2-bromoacetate (0.85 mL, 5.75 mmol) was then added dropwise, and stirring was continues at RT overnight. The reaction mixture was neutralized by addition of saturated NH4Cl, and the solution was then adjusted to pH=2-3 by addition of 0.1N HCl. The aqueous layer was repeatedly extracted with CH2Cl2, the combined organics were washed with brine, dried (phase separator) and concentrated in vacuo. The residue was dissolved in a small volume of methanol, followed by addition of water until a solid precipitated. The precipitate was filtered off, washed with water and dried in vacuo to afford the title compound as a white solid. MS (LC/MS): 306 [M+H]+, 328 [M+Na]+; tR (HPLC conditions c): 4.67 min.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=C(C3CC3)N[N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2].BrC1C=C(NC2C=[CH:58][C:57]([CH:60]3[CH2:63][N:62]([CH2:64][CH3:65])[CH2:61]3)=[CH:56]N=2)C(=O)N(C)C=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1C(=O)C2SC3CCCCC=3C=2CC1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:38]=[CH:58][C:57]([CH:60]3[CH2:63][N:62]([CH2:64][CH3:65])[CH2:61]3)=[CH:56][N:35]=2)[C:30](=[O:42])[N:29]([CH3:43])[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CCN1CC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: CCN1CC(c2ccc(Nc3cc(-c4cc(F)cc(N5CCc6c(sc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)C1
Yield: 67 %

Procedure:
Following the procedures as described for 136e and starting with 5-bromo-3-(5-(1-ethylazetidin-3-yl)pyridin-2-ylamino)-1-methylpyridin-2(1H)-one (250a) and (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 212b, compound 233a was obtained in 67% yield. LCMS: (M+H)+ 597
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[C:5]([F:19])=[CH:4][N:3]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:35])[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:35][C:2]3[N:7]=[C:6]([NH:8][CH:9]4[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[C:5]([F:19])=[CH:4][N:3]=3)[CH:26]=[C:27]([C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)[CH:28]=2)[CH2:22][CH2:21]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2F)CC(C)(C)N1
Reactant: Cn1nnnc1-c1cc(N)cc(C2CC2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: Cn1nnnc1-c1cc(Nc2ncc(F)c(NC3CC(C)(C)NC(C)(C)C3)n2)cc(C2CC2)c1
Yield: 41.6 %

Procedure:
2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine (90 mg, 0.31 mmol) was treated with 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine (80 mg, 0.37 mmol) and p-toluenesulfonic acid monohydrate (48 mg, 0.25 mmol) in isopropanol (5 mL) and heated at reflux, in a loosely capped vial, overnight. The solvent evaporated, over the course of the reaction. 2-Chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine remained in the reaction mixture. An additional equivalent of 3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)benzenamine was added, along with more isopropanol. The reaction was allowed to heat at reflux for an additional 8 hours. This process was repeated until the 2-chloro-5-fluoro-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine was consumed, 4 days later. The resulting residue was purified by column chromatography, on silica gel, eluting with methanol:methylene chloride (1:99) followed by 2M ammonia in methanol:methylene chloride (2:98), to yield N2-(3-cyclopropyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl)-5-fluoro-N4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine (60 mg, 42% yield) as an off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:24][C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (1.20 g, 5.99 mmol) and DIPEA (5.45 ml, 31.2 mmol) in dry DCM (60 ml) at 0° C. under Ar was added 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (2.04 g, 6.29 mmol) and the resulting clear solution stirred at 0° C. for 2 h. EtOAc (100 ml) and saturated aqueous NaHCO3 (100 ml) were added, the layers separated, then the organic layer washed with 2M aqueous HCl (100 ml) and passed through an hydrophobic frit. The solvent was removed to leave the title compound (2.36 g).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].CC(N(C)C)=O.[H-].[Na+].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:6]2[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]23)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 3.2 kgs. isatoic anhydride in 15 kgs. dimethylacetamide is added under nitrogen with stirring sodium hydride obtained from 880 gms. of a 57% dispersion in mineral oil, while maintaining the temperature below 25°C. The resulting mixture is heated to about 60°C. and held at about 55°-60°C. for 1 hour. The reaction mixture is then cooled to 20°-30°C. and to it is added 3.0 kgs. p-fluorobenzyl chloride. The mixture is then reheated to about 60°C. and held there for about 4 hours. It is then cooled again to 20°C. and to it is added 17.4 kgs. of ice and then 24 kgs. water. The mixture is stirred for 15 minutes, the solids collected by filtration, washed with several 2 kg. portions of water and then three times with 0.7 kg. diethylether. The washed solids are dried to obtain N-(p-fluorobenzyl)isatoic anhydride, m.p. 140°-143°C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:33][C:29]1[CH:30]=[N:31][CH:32]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=1)=[C:3]([CH3:20])[C:4]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)morpholine (40.0 mg, 0.130 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-morpholino-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.93 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.31 (1H, ddd, J=10.1, 2.5, 1.3 Hz), 6.89 (1H, d, J=12.7 Hz), 6.80 (1H, ddd, J=13.9, 8.7, 2.6 Hz), 6.58 (1H, t, J=2.4 Hz), 3.79-3.94 (8H, m), 3.33-3.41 (4H, m), 3.16 (4H, dd, J=5.7, 3.9 Hz), 2.08 (3H, s). Mass Spectrum (ESI) m/e=442.1 (M+1).