Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@@H:29]([OH:31])[CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 275 mg of (S)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.0 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromo-2-methoxybenzaldehyde (1.90 g, 8.84 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.0 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.66 g (86% yield) of tert-butyl 4-[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 385 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][C@H:40]([CH2:43][CH3:44])[CH2:41][OH:42]>>[OH:42][CH2:41][C@H:40]([NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1)[CH2:43][CH3:44]
Reactant: CC[C@@H](N)CO
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: CC[C@H](CO)NC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 58.2 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and (R)-2-amino-1-butanol (45 mg, 0.50 mmol, 1.0M in DMF) were combined to give 35 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 602 [M+H]+.
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][O:5][CH2:6][C:7]([C:10]([CH2:12][C:13]#[N:14])=[O:11])([CH3:9])[CH3:8].[OH-].[Na+]>O.C(O)C>[NH2:14][C:13]1[CH:12]=[C:10]([C:7]([CH2:6][O:5][CH3:4])([CH3:9])[CH3:8])[O:11][N:2]=1
Reactant: NO
Reactant: COCC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCC(C)(C)c1cc(N)no1

Procedure:
A solution of 58.5 g of hydroxylamine hydrochloride in 88 ml of water was added drop-by-drop over a 10-minute period to a stirred, refluxing solution of 100.9 g of 2B and 33.7 g of sodium hydroxide in 950 ml of water and 740 ml of ethanol. The mixture was stirred and refluxed for a further 18 hours, then the ethanol was evaporated in a rotary evaporator. The aqueous residue was cooled and filtered. The solid was chromatographed over silica gel, using as eluent a 2:15:33 v:v:v mixture of tetrahydrofuran, ethyl acetate and hexane, to give 3-amino-5-(1-(methoxymethyl)-1-methylethyl)-1,2-oxazole (2C), as a cream-colored solid, m.p.: 96°-99° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl.C1COCC1>[ClH:36].[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][O:13][C:14]1[CH:35]=[CH:34][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1
Reactant: O=C(Oc1cccnc1)N1CCC(Oc2ccc(O)cc2)CC1
Reactant: OCc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cl
Product: O=C(Oc1cccnc1)N1CCC(Oc2ccc(OCc3cccc(Cl)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
Diethyl azodicarboxylate (0.35 ml, 40% Tol solution) was dropwise added to a THF (5 ml) solution containing 3-pyridyl 4-(4-hydroxyphenoxy)-1-piperidinecarboxylate (160 mg), 3-chlorobenzyl alcohol (110 mg) and triphenylphosphine (200 mg) at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was diluted with chloroform, washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=1:3 (v/v)). The resulting oil was dissolved in EtOAc (5 ml), and 4 M hydrogen chloride/EtOAc solution (1 ml) was added thereto, followed by stirring at room temperature. The solvent was evaporated under reduced pressure, and the precipitated solid was recrystallized from EtOAc/2-propanol to obtain 3-pyridyl 4-{4-[(3-chlorobenzyl)oxy]phenoxy}-1-piperidinecarboxylate hydrochloride (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[C:20]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:8]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2c1CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CCN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of the product of step (b) (6.26 g, 31.4 mmol) and triethylamine (9.6 ml, 69.0 mmol) in CH2Cl2 (150 ml) was added acetyl chloride (2.7 ml, 37.7 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred at room temperature for 18 h after which time the solution was washed sequentially with H2O and saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc to afford the subtitle compound as an orange oil (6.07 g, 94%). Rf 0.65 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 206 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:26][CH2:27][CH2:28][N:29]1[C:33]([SH:34])=[N:32][N:31]=[N:30]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:34][C:33]3[N:29]([CH2:28][CH2:27][OH:26])[N:30]=[N:31][N:32]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCn1nnnc1S
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CCCSc1nnnn1CCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 63 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-(2-hydroxyethyl)-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 63% yield.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:41][CH3:42])=[C:38]([O:39][CH3:40])[C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(OC)c1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,3,4-trimethoxybenzaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 559.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14]
Reactant: C#CC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 104.3 %

Procedure:
A solution of compound of Step 6 (0.926 g, 2.85 mmol) and trifluoroacetic acid (5.49 mL, 71.3 mmol) in CH2Cl2 (5.49 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in 1.0N KOH (7 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over MgSO4 and then concentrated to give the title amine as an off-white solid (0.67 g, 100% yield). 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[N:20][C:21]=1Cl.O>O1CCOCC1>[Br:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[N:20][C:21]=1[O:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([F:13])([F:14])[F:3])=[CH:6][CH:7]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: Cn1cnc(Cl)c(Br)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc(OCc2ccc(C(F)(F)F)cc2)c(Br)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Sodium hydride (55% in mineral oil) (0.22 g) was suspended in 10 ml of dioxane, and then 0.88 g of 4-trifluoromethylbenzyl alcohol was added thereto. The resulting mixture was stirred for one hour at room temperature, then incorporated with 1.12 g of 5-bromo-6-chloro-3-methyl-4(3H)-pyrimidinone and stirred for 15 hours. The resulting solution was poured into water, and the resulting crystals were filtered off and then recrystallized from a benzene-hexane mixture to give 1.60 g of the intended product.
Reaction SMILES: CC1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=4[O:19][CH2:20][C:21](O)=[O:22])[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4]N=1.[CH3:32][CH2:33][N:34](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:65]([NH2:67])[CH3:66]>CN(C=O)C>[CH3:66][C:65]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=4[O:19][CH2:20][C:21]([NH:34][CH2:33][CH3:32])=[O:22])[N:12]4[C:28](=[O:30])[NH:29][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:31])[O:4][N:67]=1
Reactant: CCN
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1OCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)COc1ccccc1C1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of {2-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]phenoxy}acetic acid (0.03 g, 0.07 mmol) in DMF (2.0 mL) with DIPEA (0.025 mL, 0.14 mmol) and HATU (0.027 g, 0.071 mmol) was stirred at room temperature for 10 min. and ethylamine (0.0064 g, 0.14 mmol) was added. The reaction mixture was stirred for 1 h and the product was purified without workup by preparative HPLC on a C-18 column eluting with a water:MeCN gradient buffered pH 2 buffered with TFA to give the title compound as an off-white amorphous solid. LCMS calc. for C24H25N4O5 (M+H)+: m/z=449.1. found: 449.2.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[N:3]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[NH:15][Si](C)(C)C>>[CH3:13][Si:14]([NH:15][N:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][N:7]=2)[CH:2]=[N:3][CH:4]1[O:12][Si:14]([CH3:21])([CH3:20])[CH3:13])([CH3:21])[CH3:20]
Reactant: Nc1nc(=O)[nH]c2nccnc12
Reactant: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)NN1c2nccnc2C=NC1O[Si](C)(C)C

Procedure:
To 20 mL of hexamethyldisilazane (HMDS) is added 2.98 g (0.02 mole) of 4-amino-pteridine-2-one (30). The mixture is heated for 24 hours under reflux, with moisture excluded, to obtain a clear solution. The excess HMDS is removed under high vacuum to give 1-trimethylsilylamino-2-trimethylsilyloxy-pteridine as a viscous oil. The residue is dissolved in 200 mL of benzene and then 9.37 g (0.022 mole) of 2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranosyl chloride, 4 g HgO, and 4 g HgBr2 are added and the mixture is refluxed for 5 hours. After cooling, the precipitate is filtered off, the filtrate evaporated to dryness and the residue dissolved in 100 mL of CHCl3. The solution is extracted twice with 100 mL of 20% KI. The organic layer is then dried over Na2SO4, again evaporated and the residue dissolved in a little ethyl acetate for silica-gel column chromatography with ethyl acetate / acetone 7:3. The first fraction contains excess sugar, the second fraction the α-anomer and last eluting fraction the β-deoxyriboside. Evaporation and recrystallization of the residue from ethanol gives 31.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17](O)=[O:18].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][N:32]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:11][CH:12]=3)[C:2]=2[CH3:1])=[O:18])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 48.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 5-methyl-1-(4-trifluoromethylphenyl)pyrazole-4-carboxylic acid (1.1 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (1.0 g) was obtained, melting point: 274° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:29]([N:36]=[C:37]=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:37]([NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C(F)(F)F)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C(F)(F)F)ccc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH2:8]([N:15]=[C:16]=[S:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:18]I>CN(C=O)C.O>[CH3:18][S:17][CH:16]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#CCC#N
Reactant: CI
Reactant: S=C=NCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(NCc1ccccc1)C(C#N)C#N
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of malononitrile (1.21 g, 18.3 mmol) in DMF (40 ml) was added under ice-cooling sodium hydride (0.77 g, 19.2 mmol). After stirring for one hour, benzyl isothiocyanate (2.73 g, 18.3 mmol) was added dropwise. After stirring under ice-cooling for 1.5 hours, methyl iodide (2.60 g, 18.3 mmol) was added dropwise. After stirring at room temperature for 15 hours, water (400 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (100 ml×2). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a yellow oily substance (2.94 g) from the fraction from hexane-ethyl acetate (2/1). Yield=70%.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[N+](C1C=CC(S[C:17]2[C:22]([C:23]#[N:24])=[CH:21][C:20]([CH:25]=[CH:26][C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[CH:19][N:18]=2)=CC=1)([O-])=O.C(OCC)C>C(O)(C)(C)C>[NH2:4][C:3]1[N:5]=[C:23]([NH2:24])[C:22]2[CH:21]=[C:20]([CH:25]=[CH:26][C:27]3[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:33])[CH:19]=[N:18][C:17]=2[N:2]=1
Reactant: N=C(N)N
Reactant: N#Cc1cc(C=Cc2c(Cl)cccc2Cl)cnc1Sc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Nc1nc(N)c2cc(C=Cc3c(Cl)cccc3Cl)cnc2n1
Temperature: 24 °C

Procedure:
To a solution of 2.24 g (23.4 mM) of guanidine hydrochloride in 30 ml of tert.-butanol were added 0.538 g (23.4 mM) of sodium metal. The mixture was heated at 50° C. for 90 minutes, at which time 2.0 g (4.67 mM) of the 2-(4-nitrophenylthio)-3-cyano-5-(2,6-dichlorophenyl)ethenylpyridine from above were added in one portion. The mixture was heated at reflux for three hours, then cooled to 24° C., diluted by addition of 200 ml of diethyl ether, and filtered. The filter cake was washed with 30 ml of water and dried. The solid product was next washed with 20 ml of acetone and dried to afford 1.45 g (93.5% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[CH3:37][NH:38][CH3:39].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([N:38]([CH3:39])[CH3:37])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CNC
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(C(=O)N(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 56.9 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added dimethylamine (2.0 M soln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (15 mg, 57%). LC-MS m/z 528 (M+H)+; 1H-NMR (MeOD) δ 2.23 (s, 3H), 2.78 (s, 6H), 3.06 (s, 3H), 3.15 (m, 5H), 3.55 (m, 2H), 4.22 (s, 2H), 7.19 (m, 3H), 7.34 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH2:13]([OH:15])[CH3:14]>[Rh]>[CH3:3][C:11]1[CH:6]=[CH:7][C:8]([CH2:14][C:13]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])=[O:15])=[CH:9][CH:10]=1
Reactant: O=C1Nc2ccccc2C1=NO
Reactant: CCO
Agent: [Rh]
Product: Cc1ccc(CC(=O)NC2C(=O)Nc3ccccc32)cc1
Reaction time: 12 h
Yield: 18 %

Procedure:
A solution of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5% Rh/C in 300 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 1 day. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The concentrate was dissolved in 50 ml of N,N-dimethylformamide, and 5.15 g of dicyclohexylcarbodiimide, 3.83 g of 1-hydroxybenzotriazole, and 3.75 g of p-tolylacetic acid were added thereto successively. The mixture was stirred at the same temperature for 12 hours, whereupon a precipitate formed. The precipitate was filtered off, and the filtrate was concentrated. The concentrate was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to afford 1.01 g (18%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5](O)=[O:6].CCN(C(C)C)C(C)C.CN([C:27]([O:31][N:32]1N=NC2C=CC=C[C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNOC>C(Cl)Cl>[CH2:11]([C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([CH3:1])[N:10]=1)[C:5]([N:32]([O:31][CH3:27])[CH3:33])=[O:6])[CH:12]([CH3:14])[CH3:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Agent: CNOC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 2-methyl-6-(2-methyl-propyl)-isonicotinic acid (3.80 g, 16.5 mmol) in DCM (50 mL), DIPEA (10.7 g, 82.7 mmol) followed by TBTU (6.37 g, 19.9 mmol) is added. The mixture is stirred at rt for 10 min before N,O-dimethylhydroxylamine (1.94 g, 19.9 mmol) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM, washed with sat. aq. NaHCO3, followed by water, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silic gel eluting with heptane:EA 1:1 to give 2-isobutyl-N-methoxy-6,N-dimethyl-isonicotinamide (3.37 g) as a colourless oil; LC-MS: tR=0.61 min; 1H NMR (CDCl3): δ 0.95 (d, J=6.8 Hz, 6H), 2.06-2.18 (m, 1H), 2.60 (s, 3H), 2.69 (d, J=7.3 Hz, 2H), 3.37 (s, 3H), 3.57 (s, 3H), 7.13 (s, 1H), 7.18 (s, 1H).