Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])/[C:4](/[NH:16][C:17](=[O:37])[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:20][C:19]=1[Cl:36])=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.O.[OH-].[Li+]>CO.O1CCCC1.O>[Cl:36][C:19]1[CH:20]=[C:21]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:23]([CH3:24])[C:18]=1[C:17]([NH:16]/[C:4](=[CH:5]\[C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)/[C:3]([OH:38])=[O:2])=[O:37]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N/C(=C\c1cnc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
A mixture of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 211; 32 mg, 0.06 mmol) and lithium hydroxide monohydrate (11 mg, 0.262 mmol) in methanol/tetrahydrofuran/water (2:2:1; 0.25 mL) was stirred at room temperature for 48 h. An additional portion of lithium hydroxide monohydrate (6 mg, 0.14 mmol) was added and the solution was stirred for an additional 4 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of chloroform/methanol/water/acetic acid (150:30:10:6) and re-evaporated. A solution of the residual material in the same solvent mixture (1 mL) was applied to a silica gel column. The column was eluted with in turn with chloroform, chloroform/methanol/water/acetic acid (600:30:10:6), chloroform/methanol/water/acetic acid (300:30:10:6 and chloroform/methanol/water/acetic acid (150:30:10:6). The appropriate homogeneous fractions were combined, evaporated and then lyophilized to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-(quinolin-3-yl)propenoic acid (18 mg, 58% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C@@H:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:22][C@@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: N[C@H]1CCCc2ccccc21
Product: CN(C)c1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-(Dimethylamino)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone, Example 103, and 1-methanesulfonyl-piperidin-4-ylamine (with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone. MS (M+H)+, 442.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:16]([O:18][P:19](C1C=CC(C(C)C(OC)=O)=CC=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]>>[CH2:16]([O:18][P:19]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)([O:21][CH2:22][CH3:23])=[O:20])[CH3:17]
Reactant: COC(=O)C(c1ccc(Br)cc1)C(C)C
Reactant: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)C(C)C)cc1

Procedure:
Compound 13-c was prepared from 13-b in a similar manner as the synthesis of 7-f. 1H NMR (300 MHz, CDCl3) δ0.69 (d, J=6.6 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 1.20-1.39 (m, 6H), 2.31-2.39 (m, 1H), 3.17-3.23 (m, 1H), 4.04-4.20 (m, 4H), 7.42-7.45 (m, 2H), 7.71-7.78 (m, 2H). LC-MS: (M+H)+ 329.
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:14].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][CH2:32][C:31]([C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=2)=[O:33])=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: CCNCC
Solvent: c1ccccc1
Product: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Added benzene (108 mL) to anhydrous zinc(II) chloride (19.62 g, 144 mmol), followed by the addition of diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and stirred at room temperature for 2 h. Added 2-bromo-1-(4-bromophenyl)ethanone (20 g, 72.0 mmol) and 1-(4-nitrophenyl)ethanone (17.83 g, 108 mmol) together and stirred mixture for 18 h. Added 5% aq. sulfuric acid (50 mL) and stirred vigorously, then the product was collected by filtration, rinsed with benzene, water, methanol, dichloromethane and dried under vacuum to provide the product (15.0 g, 58% yield, colorless powder).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:22])[C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(Cl)(=O)C(Cl)=O.[NH3:34]>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C>[C:17]([C:16]1[CH:20]=[CH:21][C:13]([O:12][C:11]2[C:10]([Cl:22])=[C:9]3[C:4]([CH:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:6][CH2:7][O:8]3)=[CH:3][C:2]=2[Cl:1])=[CH:14][CH:15]=1)(=[O:18])[NH2:34]
Reactant: N
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(N)=O)cc1)c2Cl
Reaction time: 3 h
Yield: 80.2 %

Procedure:
4-(6,8-Dichloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation A; 150 mg, 0.365 mmol) was diluted with DCM (1.5 mL) followed by the addition of oxalyl chloride in DCM (2M) (201 μl, 0.401 mmol) and DMF (1 drop). Ammonia (6.21 mg, 0.365 mmol) was bubbled in for 10 minutes. The reaction was placed under nitrogen and stirred for 3 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated, loaded onto silica gel and eluted with neat ethyl acetate to yield ethyl 7-(4-carbamoylphenoxy)-6,8-dichlorochroman-4-carboxylate (120 mg, 0.293 mmol, 80.2% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18](C3C=CC(C(N4CCNCC4)=O)=CC=3)[CH:19]=2)[CH:3]=1.N1(C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CCNCC1.[NH2:57][CH2:58][C:59]1[CH:60]=[C:61](B(O)O)[CH:62]=[C:63]([CH3:65])[CH:64]=1>>[NH2:57][CH2:58][C:59]1[CH:60]=[C:61]([C:18]2[CH:19]=[C:14]([C:4]3[CH:3]=[C:2]([NH2:1])[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=3)[CH:15]=[N:16][CH:17]=2)[CH:62]=[C:63]([CH3:65])[CH:64]=1
Reactant: Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1
Reactant: Cc1cc(CN)cc(B(O)O)c1
Agent: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Product: Cc1cc(CN)cc(-c2cncc(-c3cc(N)nc(-c4ccccn4)c3)c2)c1

Procedure:
This compound is prepared analogously to [4-(6′-Amino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-piperazin-1-yl-methanone (Example 2.50) by replacing piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with 5″-(3-Aminomethyl-5-methyl-phenyl boronic acid (Intermediate B27).
Reaction SMILES: [CH:1]([N:4]([CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:6][NH:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:21]([C:34](Cl)=[O:35])[CH2:20][CH2:19]2.C1(C(Cl)=O)C2C(=CC=CC=2)C=CN=1>>[CH:11]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:34]([N:21]1[CH2:20][CH2:19][C:18]2[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35])([CH3:13])[CH3:12]
Reactant: CC(C)NCCN(C(C)C)C(C)C
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)Cl)CC2
Agent: O=C(Cl)c1nccc2ccccc12
Product: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)N(CCN(C(C)C)C(C)C)C(C)C)CC2

Procedure:
In a similar manner, use of equivalent quantities of N,N,N'-triisopropylethylenediamine and 6,7-dimethoxy-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarbonyl chloride in place of the dialkylaminoalkylamine and isoquinolinecarbonyl chloride employed above affords N-(2-diisopropylaminoethyl)-6,7-dimethoxy-N-isopropyl-1-phenyl-3,4-dihydro-2(1H)-isoquinolinecarboxamide.
Reaction SMILES: C1([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[C:41](I)[CH:40]=[C:39]([Cl:44])[CH:38]=1>>[Cl:36][C:37]1[CH:42]=[C:41]([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:40]=[C:39]([Cl:44])[CH:38]=1
Reactant: O=C(O)C[C@@H](C#Cc1ccccc1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Reactant: Clc1cc(Cl)cc(I)c1
Product: O=C(O)C[C@@H](C#Cc1cc(Cl)cc(Cl)c1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1

Procedure:
The procedure for the preparation of the product of EXAMPLE 18 was repeated using 1,3-dichloro-5-iodobenzene (Aldrich) in the place of iodobenzene to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.50 (1H, d); 7.45 (1H, t); 7.43 (1H, s); 7.36 (1H, s); 7.10 (1H, d); 7.03 (1H, d); 6.91 (2H, s); 6.88 (1H, t); 4.68 (1H, t); 4.04 (2H, t); 3.40 (2H, t); 2.78 (2H, d); 1.87 (4H, m).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH2:33][CH3:34])=[CH:22][C:21]3=[O:35])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH2:33][CH3:34])=[CH:22][C:21]2=[O:35])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]1
Reactant: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H]3COC(C)(C)O3)n2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C[C@@H](O)CO)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 83, 95 mg, 0.19 mmol) in tetrahydrofuran (20 mL) was treated with 2N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was diluted with ethyl acetate, washed with water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (20 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The mixture was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (51 mg, 61%) as a light yellow solid: HR-ES-MS m/z calculated for C24H32N4O6 [M+H]+ 473.2395, observed 473.2395; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.4 Hz, 3H) 0.91 (d, J=6.4 Hz, 3H) 1.24 (t, J=6.9 Hz, 3H) 1.40 (br. s., 1H) 1.46-1.62 (m, 1H) 1.64-1.80 (m, 1H) 3.17-3.40 (m, 2H) 3.69-3.79 (m, 1H) 3.79-3.90 (m, 1H) 3.98-4.11 (m, 4H) 4.49 (d, J=18.4 Hz, 1H) 4.72 (s, 1H) 4.86 (dd, J=11.0, 4.7 Hz, 1H) 6.38 (d, J=2.1 Hz, 1H) 6.97 (t, J=7.1 Hz, 1H) 7.13-7.20 (m, 1H) 7.21-7.33 (m, 2H) 7.51 (d, J=2.1 Hz, 1H) 10.72 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][C:16]=2[F:18])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(F)cc2F)cc1Cl
Yield: 28.9 %

Procedure:
In a round bottom flask, 4-bromo-2-chlorobenzonitrile (3 g, 13.85 mmol), 2,4-difluorophenylboronic acid (2.63 g, 16.63 mmol) and K3PO4 (8.83 g, 41.56 mmol) were added in dry DMF (50 mL). The mixture was purged under argon for 30 min and Pd(PPh3)4 (1.6 g, 1.38 mmol) was added. The mixture was heated for 48 hr at 80 C. Water (100 mL) was added and the aq layer was extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (3×50 mL), dried, evaporated and purified on silica gel (EtOAc/hexanes:1/19) to give the product (1 g, 29%), 1H.NMR (acetone-d6) δ: 7.2-7.28 (m, 2H), 7.72-7.79 (m, 2H), 7.91 (t, 1H, J=1.4 Hz), 8.02 (d, 1H, J=8.1 Hz).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:14][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=2)[CH2:12]1)#[N:9].[CH3:46][C@@H:47]([NH2:50])[CH2:48][CH3:49]>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:12][N:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:50][C@H:47]([CH3:46])[CH2:48][CH3:49])=[O:21])=[CH:17][CH:16]=2)[CH2:14]1)#[N:9]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5)C4)c3)ncnc21
Reactant: CC[C@@H](C)N
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 19, Step 3 started from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}benzoic acid and (2R)-butan-2-amine (Aldrich: Cat. #296651). LCMS (M+H)+: m/z=455.2. 1H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.99 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.68 (dd, J=3.3, 2.5 Hz, 1H), 7.14 (dd, J=3.4, 1.5 Hz, 1H), 6.59 (d, J=8.7 Hz, 2H), 4.55 (s, 2H), 4.30 (d, J=8.6 Hz, 2H), 3.89 (m, 1H), 3.75 (s, 2H), 1.58-1.39 (m, 2H), 1.10 (d, J=6.6 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: C1COCC1.[BH4-].[Li+].C[O:9][C:10](=O)[CH2:11][N:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CO>O>[C:13]([N:12]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11][CH2:10][OH:9])([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
In a THF solution containing 0.30 g of lithium borohydride, 1.30 g of N-(tert-butoxycarbonyl)phenylglycine methyl ester was added under ice cooling. To the resultant solution, methanol was added dropwise under ice cooling and stirred overnight at room temperature. Water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and the obtained residue was subjected to a silica gel column chromatography (hexane:ether=1:1) to give 0.41 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]3)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH3:23])[C:5]1=[O:6])[CH2:2][CH3:3]>C(O)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]3)=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH3:23])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CCC(O)C3)nc2n(CCC)c1=O
Yield: 78 %

Procedure:
0.5 g (1.6 mmol) of 1,3-dipropyl-8-(1-oxo-3-cyclopentyl)xanthine, 10 ml of ethanol and 0.1 g (2.6 mmol) of sodium tetrahydridoboranate are stirred for 21/2 days at ambient temperature. The mixture is evaporated down, in vacuo and mixed with water and methylene chloride then the aqueous phase is acidified and extracted. The combined organic extracts are dried and evaporated down in vacuo. The residue is separated into the isomers by chromatography on silica gel (CH2Cl2CH3OH 95:5). From the 1st fraction, 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 174°-176° C. and from the 2nd fraction 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 191°-193° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Al+3].[Cl-:10].[Cl-].[Cl-].[CH:13](Cl)([CH3:15])[CH3:14].Cl.C(O)C(O)C>>[Cl:10][C:3]1[C:4]([Cl:8])=[C:5]([CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(C)Cl
Reactant: Clc1cccc(Cl)c1
Reactant: [Cl-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(O)CO
Product: CC(C)c1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 10 h
Yield: 84.6 %

Procedure:
A 2 liter autoclave was charged with 1,470 g (10.0 mols of 85% strength m-dichlorobenzene (15% of p-dichlorobenzene) and 133 g (1.0 mol) of AlCl3. 413 g (5.0 mols) of isopropyl chloride were pumped in at room temperature with stirring in the course of 35 minutes during which the resulting HCl pressure was maintained at 5 bar by continuously blowing off. 15.2 g (0.2 mol) of 1,2-propanediol were added to the final 150 ml of isopropyl chloride to be pumped in, and were pumped in together with the isopropyl chloride. After the addition by pumping was complete, the autoclave was raised to 50° C. while the pressure was again maintained at a constant 5 bar by blowing off. Stirring was continued for 10 hours at 50° C./5 bar of HCl pressure. After the reaction had ended, the autoclave was cooled down, the pressure was let off, and the contents were sucked out on to 2 liters of ice-water, for hydrolysis. Stirring was continued until the mixture had become colorless, and the organic phase was then separated from the aqueous phase in a separating funnel. The subsequent distillation in a 40 cm silver-jacketed column packed with 4 mm Raschig glass rings produced a dichlorocumene mixture which passed over at 102-103° C./18 bar and consisted of 10.8% of 2,5-, 21.6% of 2,4- and 67.5% of 3,5-dichlorocumene. The yield was 84.6% of theory. 53.25% of the feed m/p-dichlorobenzene mixture was recovered (782.8 g), having a composition of 84.86% of m- and 15.14% of p-dichlorobenzene. The further conversion to 3,5-dichloro-α-methylstyrene was carried out as in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C.Cl[CH2:41][CH2:42][OH:43]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=2)[C:20]([F:23])([F:21])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:41][CH2:42][OH:43])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: OCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCO)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.25 g, 0.43 mmol) in THF (10.0 mL) was added triethylamine (0.16 mL, 1.29 mmol) and the reaction was stirred for 10 min. Then 2-chloroethanol (0.05, 0.65 mmol) was added and the reaction was stirred for 8 h at RT. The reaction mixture was diluted with ethyl acetate and washed with saturated brine solution. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as an off-white solid (0.09 g, 34%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][OH:14])[CH3:12].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:26]1[C:30](Cl)=[N:29][N:28]([CH3:32])[C:27]1=[O:33].[CH3:34][O-:35].[Na+].CO>O1CCCC1.C(OCC)(=O)C>[CH3:34][O:35][C:30]1[N:26]([C:20]2[C:19]([CH2:18][O:14][N:13]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH3:12])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:25])[C:27](=[O:33])[N:28]([CH3:32])[N:29]=1
Reactant: CC(=NO)c1ccc2ccccc2c1
Reactant: C[O-]
Reactant: Cc1cccc(CBr)c1-n1c(Cl)nn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nn(C)c(=O)n1-c1c(C)cccc1CON=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2-naphthalenyl)ethanone oxime (492 mg, 2.65 mmol) in tetrahydrofuran (7.5 mL) cooled to 0° C. under a nitrogen atmosphere was added 95% NaH (69 mg, 2.88 mmol) and the mixture was stirred for 20 min. The title compound of Step E (700 mg, 2.21 mmol) was then added to the reaction and the mixture was stirred at room temperature for 3 h. Sodium methoxide as a 30% solution in methanol (1.3 mL, 6.63 mmol) was added and the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated ammonium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (25% ethyl acetate in hexanes as eluent) to give 306 mg of the title compound of Step F, a compound of the invention, as a golden oil. 1H NMR (CDCl3): δ 2.19 (s,3H), 2.32 (s,3H), 3.41 (s,3H), 3.89 (s,3H), 5.21 (AB q,2H), 7.30 (d,1H), 7.36-7.5 (m,4H), 7.8 (m,4H), 7.97 (s,1H).