Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:44][C:45]([NH:47][CH2:48][CH:49]1[CH2:53][O:52][C:51]([CH3:55])([CH3:54])[O:50]1)=[O:46].CN(C)C=O>O>[CH3:54][C:51]1([CH3:55])[O:50][CH:49]([CH2:48][NH:47][C:45]([CH2:44][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)=[O:46])[CH2:53][O:52]1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC1(C)OCC(CNC(=O)CCl)O1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 24 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 300 mg, 487 μmol) and 2-chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide (101 mg, 487 μmol) were combined with dry dimethyl formamide (5 mL) to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with methanol in ethyl acetate) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-carbamoyl]-methyl ester as an off-white solid (92 mg, 24% yield). LCMS (ES+) m/z calcd. for C39H42Cl2F2N4O7 [(M+H)+]: 787. found: 787.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:26]([CH2:27][CH3:28])=[CH:25][C:7]2[NH:8][C:9]([C:11]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[C:26]([CH2:27][CH3:28])=[CH:25][C:7]2[NH:8][C:9]([C:11]3[C:15]([NH2:16])=[CH:14][N:13]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[N:12]=3)=[N:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3[N+](=O)[O-])[nH]c2cc1CC
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc2nc(-c3nn(C4CCCCO4)cc3N)[nH]c2cc1CC
Reaction time: 96 h
Yield: 40.7 %

Procedure:
A solution of 5-ethoxy-6-ethyl-2-[4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazol-3yl]-1H-benzoimidazole [0.8 g, Reference Example 50(a)] in ethanol (100 mL) was treated with palladium on carbon (0.1 g, 10%) and mixture was hydrogenated at atmospheric pressure (balloon) for 4 days. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 0-10% methanol) to give 3-(5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine (0.3 g) as a solid. LC-MS (Method E): RT=2.15 minutes, 356 (M+H)+. (b) 4-chloro-5-methoxybenzene-1,2-diamine
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH3:23][O:22][C:20](=[O:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: BrC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.65 g (32.5 mmol) of potassium tert-butoxide in 65 ml of abs. DMF was cooled to 0° C., and a solution of 5.0 g (27.08 mmol) of methyl 4-chlorophenylacetate in about 2 ml of abs. DMF was added dropwise. The mixture was stirred at 0° C. for 30 min, and 4.84 g (32.5 mmol) of cyclopentyl bromide were then slowly added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then added to water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 6.28 g of the target compound (91.8% of theory).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][C:11]2[C:6](=[C:7]([OH:15])[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:3]1([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=[C:9]([CH:13]=[O:14])[CH:10]=2)[C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCC1(Cc2ccccc2)CC(=O)c2c(O)cc(C=O)cc2C1
Product: CCC1(Cc2ccccc2)CC(=O)c2c(cc(C=O)cc2OCc2ccccc2)C1

Procedure:
The product of Example 35 is benzylated with benzyl bromide as described in Example 15.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.CCN(CC)CC>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccncn1
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A solution of chloroacetyl chloride (1.22 mmol) in anhydrous CHCl3 (2.4 mL) was added slowly to a mixture of 4-aminopyrimidine (1.11 mmol) and Et3N (1.66 mmol) in anhydrous CHCl3 (22 mL) at room temperature. The bright yellow mixture gradually turned orange and after 4 hr the reaction was quenched with H2O (1 mL). After stirring for 15 min the mixture was concentrated to dryness under reduced pressure and the residue purified by flash silica gel chromatography (1-2% MeOH/dichloromethane) to give a yellow solid (122 mg).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)=[O:26]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCBr)Nc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.30 mL) and 4-aminobenzotrifluoride (1.21 g) were stirred in dichloromethane (35 mL) at 0° C. under nitrogen and treated with 6-bromohexanoyl chloride (1.15 mL). After 20 minutes, the reaction was allowed to warm to 20° C. and stirred an additional 40 minutes. The reaction was treated with aqueous saturated sodium bicarbonate (40 mL), and extracted with dichloromethane. The extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a solid. This solid was dissolved ethyl acetate and the title compound was precipitated out as fine white needles by addition of hexanes (2.35 g). M.p. 96°-98° C. Anal. Calc. for C13H15BrF3NO: C, 46.17; H, 4.47; N, 4.14. Found: C, 46.25; H, 4.59; N, 4.12. IR(KBr): 3316, 1670, 1600, 1530, 1410, 1322, 1260, 1170, 1128, 1112, 1066, 842 cm-1. CIMS(CH4): 340 (90%), 338 (100%), 320 (50%), 318 (55%), 258 (60%). 1H NMR (CDCl3): 7.65 (2H, d; J=8.5 Hz), 7.56 (2H, d; J=8.5 Hz), 7.47 (1H, bs), 3.42 (2H, t; J=6.5 Hz), 2.40 (1H, t; J=6.6 Hz), 1.90 (2H, m), 1.75 (2H, m), 1.52 (2H, m) ppm. 13C NMR (CDCl3): 171.21, 140.83, 126.27, 119.32, 37.39, 33.49, 32.34, 27.64, 24.42 ppm. 19F NMR (CDCl3): -62.712 ppm.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH:26]1([N:29]([CH3:37])[C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]([CH3:37])[C:30]2[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]3[O:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[Br:22])=[N:13][C:12]=3[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:34][CH:35]=2)[CH2:28][CH2:27]1
Reactant: CN(c1ccc(N)cn1)C1CC1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1ccc(N(C)C2CC2)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-cyclopropyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H23BrN4O2 (m/e) 455, obsd 456 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.C([O-])(O)=O.[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1
Reactant: COc1ccc2c(n1)NC(=O)CN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc2c(n1)NC(=O)CN2C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 99.2 %

Procedure:
To a solution of 6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (6.35 g, 35.4 mmol) in EtOAc (600 ml)/NaHCO3 (sat. solution) (200 ml) stirred vigorously was added at room temperature benzyl chloroformate (5.31 ml, 37.2 mmol). After 45 minutes the reaction was complete. The layers were separated and the organic layer was dried over MgSO4, filtered and evaporated to afford the desired product as an off-white solid (11 g, 99%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:20])[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:11][CH:10]=1)[CH3:2].N1C=CC=CC=1.[C:27]1([S:33]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH2:1]([N:3]([S:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:4](=[O:20])[O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:13][CH:14]=1)[CH3:2]
Reactant: ClSc1ccccc1
Reactant: CCNC(=O)OCCOc1ccc(OC(C)CC)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)Oc1ccc(OCCOC(=O)N(CC)Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethylcarbamate (1.50 g, 5.34 mmol) and pyridine (1 ml, 11.75 mmol) in 20 ml of methylene chloride at RT is added phenylsulfenyl chloride (1.54 g, 10.70 mmol). The reaction mixture is stirred for 2 hours, after which it is poured into ice water and extracted with ether. The combined organic layers are washed with 10% HCl, with water until neutral and with brine and dried. After filtration and removal of the solvent, the product is purified by prep. TLC to give O-2-[4-(1-methylpropoxy)phenoxy]ethyl N-ethyl-N-phenylsulfenylcarbamate, MS m/e 390 (M+ +H) (compound 23, Table A).
Reaction SMILES: C([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH2:11][O:12][CH3:13])[CH2:9]O)(C)(C)C.O1CCCC1.CC(C)([O-])C.[K+]>O>[CH3:13][O:12][CH2:11][C@H:8]1[CH2:9][O:14][C:6](=[O:5])[NH:7]1
Reactant: COC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl[(2R)-1-hydroxy-3-methoxypropan-2-yl]carbamate (synthesized according to the procedure described in Sowinski, J. A.; Toogood, P. L. J. Org. Chem. (1996), 61(22), 7671-7676) (8.3 g, 40.4 mmol) tetrahydrofuran (100 mL), 1M solution of potassium t-butoxide in tetrahydrofuran (80.9 mL, 80.9 mmol) was added dropwise at 0° C. and the mixture was stirred at the room temperature for 2 hours. Water (20 ml) was added to the reaction mixture and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and dried over Na2SO4. Yield: 5.0 g (94%). 1H NMR (300 MHz, DMSO-d6) δ: 3.3 (s, 3H), 3.3 (m, 2H), 3.9 (m, 1H), 4.0 (dd, 1H), 4.3 (t, 1H), 7.7 (d, 1H). [α]D25=−5.876.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]=3[CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17][C:16]=3[CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]
Reactant: CN(C)S(N)(=O)=O
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(COc2ccc3c(c2)CC(C)(C)CC3)cc1F
Yield: 22.2 %

Procedure:
A solution of 5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (326 mg, 0.20 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.20 mmol) and 4-dimethylaminopyridine (38 mg, 0.20 mmol) in DCM (3 mL) was stirred at room temperature for 16 hrs. The reaction was quenched with water (5 mL), adjusted pH to 5 with HCl (1M) and extracted with DCM (30 mL×3). The combined organic layers were concentrated and purified by reverse phase combiflash (20%-50% MeCN in 0.1% formic acid) to give the desired product (14.6 mg, 19%) as a white solid. LCMS (ESI) Method A: RT=6.47 min, m/z 466.9 [M−H]+; 1H-NMR (500 MHz, MeOD-d4) δ 7.63 (d, J=5.5 Hz, 1H), 7.32 (d, J=11.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.66-6.63 (m, 1H), 6.56 (d, J=2.0 Hz, 1H), 5.03 (s, 2H), 2.83 (s, 6H), 2.64 (t, J=13.0 Hz, 2H), 2.40 (s, 2H), 1.46 (t, J=13.5 Hz, 2H), 0.88 (s, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:36](=[O:38])[CH3:37])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was placed in 1 ml DCM and treated with DIPEA (0.04 ml; 0.23 mmol) and acetyl chloride (0.04 ml; 0.57 mmol). It was stirred at ambient temperature for 4 hours. The crude reaction mixture was purified by using reversed phase chromatography under acid conditions.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].C(OCC)(=O)C>Cl.O>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:5](=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=2)[N:6]=1
Reactant: C/C=C/C=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
To a solution of 3-(trifluoromethyl)aniline (12.43 mL, 99.92 mmol) in 6 N HCl (50 mL) in water was added (E)-but-2-enal (18.77 mL, 229.8 mmol) dropwise at reflux. The reaction was stirred at reflux for 3 hours. After cooling to ambient temperature, ethyl acetate (200 mL) was added. The aqueous layer was separated, basified with ammonium hydroxide to about pH 9, and extracted with DCM (2×200 mL). The combined organic layers were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give 2-methyl-7-(trifluoromethyl)quinoline (6.1 g, 28.9%) as a solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([NH:19][CH3:20])=[O:18])[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([NH:19][CH3:20])=[O:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CNC(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1F
Product: CNC(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzamide (A-35) and 2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=390.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CCCCCC>C(OCC)C>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][Cl:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CO)S1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CCl)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-hydroxymethyltetrahydrothiophene (compound No. 1-5, 5.0 g) in anhydrous diethylether (80 ml), triphenylphosphine (9.7 g) and carbon tetrachloride (5.7 g) are added under nitrogen atmosphere and the mixture is stirred for 2 hours at room temperature. n-Hexane (200 ml) is added to the mixture and filtrated. The filtrate is concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-chloromethyltetrahydrothiophene.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[C:14]1[C:15]2[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH2:2][CH3:3].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:6]4[C:7]5[O:11][CH2:10][O:9][C:8]=5[CH:12]=[CH:13][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A70) and commercially available 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC=C([Cl:53])C=3)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:53])[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 461 (1.40 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:6 as the eluent to afford the title compound as yellow syrup.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].CN(C)C=O.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:26])=[O:15])=[CH:12][CH:11]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)Cl)cc1

Procedure:
62.56 g of 4-methacryloyloxyethyloxybenzoic acid was charged to a flask with 0.5 g dimethyl formamide , and 54.38 ml of thionyl chloride was added dropwise under stirring. The reaction was exothermic. The reaction mixture was stirred overnight to give a clear brownish solution. The excess thionyl chloride was drawn off under vacuum. The residue was digested once with 20 ml of distilled toluene, and the toluene drawn off under vacuum. The residue was directly usable.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[C:10]([F:29])=[CH:11][C:12]([F:28])=[C:13]([C@:15]4([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=O)[NH:16]4)[CH:14]=3)[O:8][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[C:10]([F:29])=[CH:11][C:12]([F:28])=[C:13]([C@:15]4([CH3:27])[C:21]([F:23])([F:22])[C:20]([CH3:25])([CH3:24])[O:19][CH2:18][C:17](=[S:41])[NH:16]4)[CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)c(F)cc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)c(F)cc2F)C1(F)F
Yield: 87.2 %

Procedure:
The reaction of (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (164 mg, 359 μmol) with Lawesson's reagent (145 mg, 359 μmol) in 1,4-dioxane (3.5 ml) yielded the (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-thione (148 mg, 87% yield) as a white solid. MS (ISP): m/z=473.0 [M+H]+ and 475.1 [M+2+H]+.
Reaction SMILES: CO[C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[C:7]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:8][C:9](SC)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].[Na].[CH2:31]([OH:34])[CH2:32][OH:33]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:6]2[CH:5]=[CH:4][C:3](=[O:29])[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:7]=2[N:8]=[C:9]([O:33][CH2:32][CH2:31][OH:34])[N:10]=1
Reactant: OCCO
Reactant: COC(=O)/C=C/c1c(Nc2ccccc2Cl)nc(SC)nc1-c1ccccc1Cl
Agent: [Na]
Product: O=c1ccc2c(-c3ccccc3Cl)nc(OCCO)nc2n1-c1ccccc1Cl

Procedure:
Prepared as described above in Example 98 starting from (E)-3-[4-(2-chloro-phenylamino)-6-(2-chloro-phenyl)-2-methylsulfanyl-pyrimidin-5-yl]-acrylic acid methyl ester and ethylene glycol sodium salt to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(2-hydroxy-ethoxy)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 3.81 (m, 2H), 4.23 (m, 2H), 5.62 (m, 0.5 H), 6.65 (d, 1H, J=9.6 Hz), 7.29-7.58 (9H). LC MS (m/e)=428 (MH+). Rt=1.85 min