Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH:15]=O)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:1]1([CH2:7][O:8][C:9]2[C:10](/[CH:15]=[CH:21]/[C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ncccc1OCc1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COC(=O)/C=C/c1ncccc1OCc1ccccc1
Yield: 712.6 %

Procedure:
Crude 3-(phenylmethoxy)-2-pyridinecarboxaldehyde (30 g) and carbomethoxymethylenetriphenylphosphorane (55 g) in acetonitrile (800 ml) were stirred at reflux overnight. The solution was evaporated onto silica (Merck 9385) which was then purified by FCC eluting with ethyl acetate to give the product contaminated with triphenylphosphine oxide. This crude product was triturated with ether and the triturate was evaporated to an oil which was chromatographed on a column of silica (Merck 9385) eluting with cyclohexane followed by cyclohexane/ethyl acetate (4:1) to give the title compound as a yellow oil (270 g), t.l.c. (cyclohexane/ethyl acetate/triethylamine 80:20:1) Rf 0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20]([OH:33])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:33][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:32])([CH3:31])[CH3:30])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](CCc1ccccc1C(C)(C)O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100 gm) in dichloromethane (500 ml) at 25-30° C. 4-di(methyl amino)pyridine (5.32 gm) was added and cooled to 0° C. To the reaction mixture Triethylamine (26.4 gm) was added at 0° C. Acetic anhydride (26.7 gm) was added slowly at temp. 0-5° C. over 30-60 min and maintained the reaction at temp. 0-5° C. over 30 min. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3(500 ml) and stirred for 15 min. Temperature was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and separated the organic layer. Aq.layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 25% NH4Cl solution (500 ml). Organic layer was distilled below 40° C. to get the desired product as residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:33][C:34](=[O:47])[C@@H:35]([O:44][CH2:45][CH3:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[CH3:32]>C1C=CC=CC=1>[CH2:31]([O:33][C:34](=[O:47])[C@@H:35]([O:44][CH2:45][CH3:46])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:11][CH2:10]/[CH:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)\[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:39][CH:38]=1)[CH3:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(\c1ccccc1)c1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\c2ccccc2)c2ccc(Br)cc2)cc1)OCC
Yield: 90.3 %

Procedure:
Reaction of (E)-3-(4-bromophenyl)-3-phenyl-prop-2-en-1-ol (289 mg, 1.0 mmol), tributylphosphine (0.37 ml, 1.5 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.10 mmol) and azodicarboxylic dipiperidide (378 mg, 1.5 mmol) in benzene in an identical manner to example 3 gave the title compound (460 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[C:18]1([S:24]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=O)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:32][C:28]3[N:27]([S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])[CH:31]=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccn1S(=O)(=O)c1ccccc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cccn1S(=O)(=O)c1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 1-(phenylsulfonyl)-1H-pyrrole-2-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:24])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:24])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 29d (100 mg, 0.35 mmol) in THF (2 mL) was added oxalyl dichloride (46 μL, 0.53 mmol) dropwise at 0° C., followed by addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, and was then warmed up to room temperature overnight. The solvents were removed under reduced pressure, and the residue, compound 29e, was dried under reduced pressure for 2 h and then used in the next step without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].CCN(C(C)C)C(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[C:23]1[S:24][C:25]2[C:26]([NH2:33])=[N:27][CH:28]=[C:29]([F:32])[C:30]=2[N:31]=1>C1COCC1>[CH3:5][O:4][C:2](=[O:3])[NH:33][C:26]1[C:25]2[S:24][C:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])=[N:31][C:30]=2[C:29]([F:32])=[CH:28][N:27]=1
Reactant: COC(=O)Cl
Reactant: Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(F)c2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
To a solution of methyl chloroformate (18 mg, 0.191 mmol) and DIPEA (42 μL, 0.24 mmol) in THF (1.0 mL) was added 2-(2,6-dichlorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-ylamine (50 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then heated at 50° C. for 2 hours and left standing at room temperature for 18 hours. The crude reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a white solid (12 mg, 20%). 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 7.77-7.65 (m, 3H), 3.73 (s, 3H). LCMS (Method C): RT=4.74 min, m/z: 372 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(N(CC)CC)C.Cl[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:24]>O1CCCC1>[C:25]1([C:23]([O:1][C:2]2[CH:7]=[C:6]([Si:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[CH:4][C:3]=2[C:12](=[O:14])[CH3:13])=[O:24])[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(=O)c1ccc([Si](C)(C)C)cc1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)Oc2cc([Si](C)(C)C)ccc2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Under ice-cooling, to a solution of 832 mg (4 mmol) of 2'-hydroxy-4'-trimethylsilylacetophenone in 20 ml of tetrahydrofuran were added dropwise successively, 0.61 ml (4.4 mmol) of triethylamine and 874 mg (4.4 mmol) of methyl p-chloroformylbenzoate with stirring. The mixture was stirred at room temperature for 1 day and filtered. The filtrate was evaporated and the residue was dissolved in AcOEt. The organic solution was washed with H2O, aqueous sodium bicarbonate solution and brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (5:1)] to give 1.40 g of pale yellow viscous liquid (yield 95%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][O:39][C:36]2[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCOc3ccc(Cl)cc3)c2)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a stirred solution of 3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide (24 mg, 0.05 mmol) and 4-chlorophenol (128 mg, 1 mmol) in DMF (1 mL), was added K2CO3 (138 mg, 1 mmol) and the mixture was stirred at 100° C. for 2 h. The mixture was cooled and the solids were filtered off. The filtrated was concentrated and purified by preparatory HPLC, to provide the product as a beige solid (10 mg, 38%). HPLC (4 minute 10-90 gradient) tR 2.77 min; MS m/z 531.21 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:42]3[CH2:41][CH2:40][N:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[OH:51])[CH2:44][CH2:43]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (462 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH3:20]>CN(C=O)C>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:19][CH3:20])[C:3]([O:2][CH3:1])=[O:12]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1Cl
Temperature: 70 °C
Yield: 97.7 %

Procedure:
Methyl-4-hydroxy-3-chlorobenzoate (10 g, 53.6 mmol) and potassium carbonate (14.8 g, 107.2 mmol) were suspended in DMF (110 ml) and then ethyl iodide (8.56 ml, 107.2 mmol) was added. The reaction mixture was heated to 70° C. overnight. The reaction mixture was filtered and the residue washed with ether. The organic solutions were evaporated in vacuo and then dissolved in EtOAc and washed with aq. NaOH and water, dried and evaporated to dryness in vacuo to afford the title compound (11.24 g) as a yellow oil. MS (ES): C10H1135ClO3 requires 214; found (MH+) 215.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:31])[CH:30]=1)[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:23]=[C:22]([F:21])[CH:30]=[C:29]([F:31])[CH:28]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(F)cc(F)c1
Agent: Cl
Product: O=C(CNC(=O)c1cc(F)cc(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,5-difluorobenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][N:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][N:14]=1)=[O:9]
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(-c2ccccc2)[nH]n1)c1cc(Br)ccc1O
Yield: 9.2 %

Procedure:
Using 5-bromosalicylic acid and 3-amino-5-phenylpyrazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23](/[C:29]#[N:30])=[CH:24]\[C:25]([F:28])([F:27])[F:26]>C(#N)C>[F:26][C:25]([F:28])([F:27])[CH:24]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:23][C:29]#[N:30]
Reactant: N#C/C=C/C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
To a flask equipped with a mechanical stirrer, nitrogen inlet and thermowell was added compound 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 1424 g, 4.52 mol) and acetonitrile (14 L). The resulting suspension was added 4,4,4-trifluorocrotonitrile (32, 601.6 g, 4.97 mol, 1.1 equiv) followed by 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU, 67 mL, 0.452 mol, 0.1 equiv). A slight exotherm (5° C.) was noted upon the addition of the DBU. The reaction mixture was stirred at room temperature for 30 minutes when TLC and LCMS showed the reaction was deemed complete. The reaction mixture was then concentrated under reduced pressure to remove most of the solvent and the residue was purified by two silica gel columns (3 Kg each) for chromatography purification. The column was eluting with 2:1 heptane/ethyl acetate (30 L) followed by 1:1 heptane/ethyl acetate (30 L). The fractions containing pure desired product (33) were combined and concentrated under reduced pressure to afford racemic 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, Racemic SEM-protected compound, 1802 g, 1973 g theoretical, 91.3% yield) as a thick oil, which was directly used in subsequent chiral column separation without further purification. For 33: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.99 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 7.80 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 6.05 (m, 1H), 5.63 (s, 2H), 3.82 (dd, 1H, J=17.5, 10.6 Hz), 3.66 (dd, 1H, J=17.0, 4.9 Hz), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.2 Hz), −0.145 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.7, 151.3, 149.5, 140.8, 132.9, 130.4, 123.2 (JCF=282 Hz), 121.9, 116.2, 113.5, 100.2, 72.3, 65.7, 57.8 (JCF=32.4 Hz), 17.1, −1.46; C19H23F3N6OSi (MW, 436.51), LCMS (EI) m/e 437 (M++H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7]Cl)(=[O:5])=[O:4])[CH3:2].[CH2:9]([NH2:13])[CH2:10][CH2:11][CH3:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][NH:13][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCCCN
Reactant: CCS(=O)(=O)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNCCS(=O)(=O)CC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of 15.7 g of chloroethyl ethyl sulfone in 50 ml of toluene is added dropwise within 10 min to a solution of 73 g of n-butylamine and 10.1 g of triethylamine in 100 ml of toluene at an internal temperature of 50° C. The mixture is stirred at 50° C. for 5 h and allowed to cool to room temperature, the precipitate is filtered off with suction, and the filtrate is concentrated in a rotary evaporator. The remaining yellow oil (18.7 g) is reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=3)[NH:22][C:20]=2[N:21]=1.CN(C=O)C>C(O)CCC>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)=[CH:3][C:2]([NH:1][C:18]2[C:19]3[CH:24]=[C:23]([C:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=4)[NH:22][C:20]=3[N:21]=[CH:16][N:17]=2)=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3cnc(Cl)nc3[nH]2)CC1
Reactant: Cn1cc(N)cc(-c2cncs2)c1=O
Solvent: CN(C)C=O
Solvent: CCCCO
Product: Cn1cc(Nc2ncnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)cc(-c2cncs2)c1=O
Temperature: 120 °C
Reaction time: 15 h

Procedure:
5-Amino-1-methyl-3-thiazol-5-yl-1H-pyridin-2-one (99.0 mg, 0.478 mmol) was added to a solution of tert-butyl 4-(chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (133 mg, 0.398 mmol) in 1-butanol (2.0 L). The reaction was stirred at 120° C. for 15 h. DMF (1.5 mL) was added and the mixture was filtered. The filtrate was purified by HPLC to yield the title compound. 1H-NMR (CD3OD, 400 MHz): δ=1.50 (s, 9H), 2.57 (m, 2H), 3.67 (m, 2H), 3.73 (s, 3H), 4.13 (m, 2H), 6.30 (s, br, 1H), 6.62 (s, 1H), 8.21 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.99 (s, 1H). MS (ES+): m/z 506.08 [MH+]. HPLC: tR=2.62 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1

Procedure:
To a suspension of 6-chloronicotinoyl chloride (10.5 g, 59.7 mmole) in dry dichloromethane (100 mL) was added 4-fluoroaniline (5.6 mL, 59.7 mmole), followed by the dropwise addition of N,N-diisopropylethylamine (21 mL, 19 mmol).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[C:19]1([N+]#N)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)C>[C:1]1([C:7]([CH2:9][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#[N+]c1ccccc1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
0.97 mmol of (1-phenylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The resulting mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5 N hydrochloric acid, water and a saturated aqueous solution of common salt, successively. The organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.68 mmol of benzyl phenyl ketone.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][C:13]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10]>CN(C=O)C.C(Cl)Cl>[C:9]([C:12]1[C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:16]([Br:1])[CH:17]=1)(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc(C(C)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
N-Bromosuccinimide (0.756 g, 4.27 mmol) was added portionwise to a solution of N-(4-acetyl-3-benzyloxy-phenyl)-acetamide (1.2 g, 4.24 mmol) in DMF (24 ml) and the reaction stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and dried over MgSO4 to afford a white solid (1.03 g, 67%). LC/MS: RT=2.609 min. 362/364 (MH+).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH3:8][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[NH:30][CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:10].C(OC=O)=O>C1COCC1>[CH:1]([N:30]1[C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][CH:9]([CH3:8])[CH3:10])=[CH:16][CH:17]=3)=[CH:35][C:25]=2[CH:26]=[C:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][CH2:29]1)=[O:3]
Reactant: CC(=O)O
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2NCC1
Agent: O=COC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(C=O)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.51 ml) was added formic acid, (0.25 ml) at 0° C., and the mixture was stirred at 55° C. for 2 hours, air-cooled and diluted with THF (10 ml). In THF (15 ml) was dissolved methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (462 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous, magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (496 mg) as white crystals.