Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][CH:5]=[O:6].P(Cl)(Cl)(Cl)=O.[CH2:13]([N:18]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:19]([C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:29]=[C:23]2[N:22]=1)=[O:20])[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl.O>[CH2:38]([N:18]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:19]([C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:29](/[CH:3]=[CH:4]/[CH:5]=[O:6])=[C:23]2[N:22]=1)=[O:20])[CH2:39][CH:40]([CH3:42])[CH3:41]
Reactant: CN(C)C=CC=O
Reactant: COc1ccc(-c2cc3nc(C(=O)N(CCC(C)C)CCC(C)C)ccn3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)nc3c2/C=C/C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(dimethylamino)acrolein (0.22 mL; 218 mg; 2.2 mmol) in N,N-dimethylformamide (3 mL) was added phosphoryl chloride (0.16 mL; 269 mg; 1.76 mmol) and the mixture was stirred at room temperature for 10 min. Then N,N-diisopentyl-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-5-carboxamide (180 mg; 0.44 mmol) in N,N-dimethylformamide (2 mL) was added and the mixture was heated to 65° C. for 4 h. Then triethylamine (2 mL) and water (2 mL) were slowly added at 60° C. and the mixture was stirred for 30 min. The mixture was cooled to room temperature and diluted with methylene chloride and water. The aqueous layer was back extracted with methylene chloride and the combined organic layers were washed with water (3×10 mL), brine and concentrated. The residue was purified by flash-chromatography using 5% methanol in methylene chloride as eluant. LCMS m/z 463.3 (M+H)+, ret. time=2.98 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(O)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)O)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 1-1) and 1-aminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, CD3OD) δ ppm 7.99 (dd, J=7.71, 1.14 Hz, 1 H), 7.84 (d, J=7.07 Hz, 1 H), 7.71 (s, 1 H), 7.64 (td, J=7.58, 1.26 Hz, 1 H), 7.55 (d, J=8.59 Hz, 1 H), 7.50-7.41 (m, 1 H), 7.37 (dd, J=8.59, 1.52 Hz, 1 H), 6.03 (s, 1 H), 5.16 (s, 2 H), 4.08 (dd, J=11.49, 6.44 Hz, 1 H), 3.62 (t, J=4.80 Hz, 2 H), 3.44-3.35 (m, 4 H), 2.42 (s, 3 H), 1.33 (d, J=6.06 Hz, 3 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1C=C(O)C=CC=1C.[F:21][C:22]([F:45])([F:44])[C:23]1[O:27][C:26]([CH2:28][N:29]2[C:37]3[CH:36]=[C:35]4[O:38][CH2:39][CH2:40][O:41][C:34]4=[CH:33][C:32]=3[C:31](=[O:42])[C:30]2=[O:43])=[CH:25][CH:24]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:42][C:31]1([C:9]2[C:8]([OH:11])=[CH:7][C:3]3[O:4][CH2:5][CH2:6][O:1][C:2]=3[CH:10]=2)[C:32]2[CH:33]=[C:34]3[O:41][CH2:40][CH2:39][O:38][C:35]3=[CH:36][C:37]=2[N:29]([CH2:28][C:26]2[O:27][C:23]([C:22]([F:44])([F:45])[F:21])=[CH:24][CH:25]=2)[C:30]1=[O:43]
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc21)OCCO3
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCCO2)OCCO3

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 3,4-dimethylphenol, and 6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one was obtained (80%): 1H NMR (300 MHz, CDCl3) δ8.78 (s, 1H), 7.07-6.97 (m, 1H), 6.71-6.65 (m, 1H), 6.60-6.55 (m, 1H), 6.51-6.47 (m, 1H), 6.40-6.35 (m, 1H), 6.31-6.25 (m, 1H), 4.89-4.69 (m, 2H), 4.34-4.04 (m, 9H); MS (ES+) m/z 487.9 (M−17).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12]>O>[C:8]([OH:15])(=[O:14])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:12])=[O:5]
Reactant: O=C1C=CC(=O)O1
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Product: O=C(O)/C=C\C(=O)O

Procedure:
adding water to the dehydrator bottoms stream to convert a portion of the maleic anhydride to fumaric acid and then cooling the dehydrator bottoms stream comprising molten maleic anhydride, entrainer, and fumaric acid to a temperature of about 250° F. to about 310° F. to precipitate the fumaric acid and form a slurry of fumaric acid in molten maleic acid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(N2Cc3ccccc3NC2=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Nc2ccccc2CN1c1ccc(O)c(F)c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-(3-fluoro-4-methoxyphenyl)-3,4-dihydroquinazolin-2(1H)-one (60 mg, 0.22 mmol) in 2.2 mL dichloromethane at 0° C. under a drying tube was added boron tribromide (104 μL, 1.1 mmol) neat by syringe. After 5 minutes, TLC in 1/1 EtOAc/hexanes showed complete consumption of starting material and a new slightly lower rf spot. The reaction was quenched by pouring into saturated NaHCO3 (30 mL) with stirring. 9/1 Dichloromethane/methanol (30 mL) was added and the mixture stirred rapidly. The layers were separated and the organics were dried (MgSO4), filtered, and concentrated to a white solid (40 mg, 70%). LRMS (APCI pos) m/e 259 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 1H), 7.22 (m, 1H), 7.07 (m, 2H), 6.98 (m, 2H), 6.83 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+].CO.C(OC)=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:13])[CH2:14][N:15]=[N+:16]=[N-:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCCOCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCCc1ccccc1
Yield: 93.5 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 5.77 g of 3-phenylpropoxymethyloxirane (prepared as described in Preparation 52), 9.75 g of sodium azide, 160 ml of an 8:1 by volume mixture of methanol and water and 40 ml of methyl formate were used, to give 6.6 g of the title compound as a pale yellow oil having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: FC(F)(F)OC1C=C(N[C@@H](C)C(O)=O)C=CC=1.COC(OC)CNCCCCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1.[F:45][C:46]([F:80])([F:79])[O:47][C:48]1[CH:49]=[C:50]([NH:54][C@@H:55]([CH3:78])[C:56]([N:58]([CH2:72][CH:73](OC)OC)[CH2:59][CH2:60][CH2:61][CH2:62][N:63]2[CH2:70][CH2:69][C:66]3([CH2:68][CH2:67]3)[C@H:65]([OH:71])[CH2:64]2)=[O:57])[CH:51]=[CH:52][CH:53]=1>>[OH:71][C@@H:65]1[CH2:64][N:63]([CH2:62][CH2:61][CH2:60][CH2:59][N:58]2[CH2:72][CH2:73][N:54]([C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([O:47][C:46]([F:79])([F:80])[F:45])[CH:49]=3)[C@@H:55]([CH3:78])[C:56]2=[O:57])[CH2:70][CH2:69][C:66]21[CH2:68][CH2:67]2
Reactant: COC(CN(CCCCN1CCC2(CC2)[C@H](O)C1)C(=O)[C@H](C)Nc1cccc(OC(F)(F)F)c1)OC
Agent: CC[Si](CC)(CC)O[C@@H]1CN(CCCCNCC(OC)OC)CCC12CC2
Agent: C[C@H](Nc1cccc(OC(F)(F)F)c1)C(=O)O
Product: C[C@H]1C(=O)N(CCCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(OC(F)(F)F)c1

Procedure:
The title compound was produced in analogy with example 94, steps E and F. Thus, (S)-2-(3-trifluoromethoxy-phenylamino)-propionic acid (intermediate 25) was coupled in step E with (2,2-dimethoxy-ethyl)-[4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-amine (example 94D), leading to (S)-2-(3-trifluoromethoxy-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-propionamide, which was converted to the title compound in step F. Light yellow gum, MS: 456.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24].CCCCCCC>C(O)(C)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:24][C@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Reactant: CC(C)(Br)c1ccccc1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc(-c2ccn(C[C@@H](C)c3ccccc3)n2)sc1C(=O)NCc1ccccc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide and 2-(bromo-1-methyl-ethyl)-benzene as described in Example 90 and isolated by chiral separation (90:10, heptane:isopropyl alcohol). 1H NMR (400 MHz, CDCl3) δ 7.20-7.39 (m, 8H), 7.13 (d, J=4 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.68 (d, J=2 Hz, 1H), 5.98-6.04 (bm, 1H), 4.62 (d, J=8 Hz, 2H), 4.17-4.32 (m, 2H), 3.33-3.44 (m, 1H), 2.75 (s, 3H), 1.29 (d, J=4 Hz, 3H); MS (M+H)+=417.2; Rt=1.32 min; HRMS (M+H)+=417.17.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH3:14])[C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)CCC.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH2:13][CH3:14])[CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])#[N:12]
Reactant: CCC(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCCCO
Product: CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 2-(4-nitrophenyl)butyronitrile (10.0 g), butanol (10 ml) and methyl acrylate (5.2 ml) was cooled to 10° C. in a 100 ml 3-necked round-bottomed flask, equipped with a magnetic follower. A solution of potassium tert-butoxide (0.6 g) in tert-butanol (10 ml) was added dropwise, maintaining the temperature at approximately 10° C. (solution turns purple). After addition was complete, the mixture was allowed to reach ambient temperature and then stirred for a further 2 hours. The reaction was worked-up by partitioning between diethyl ether (400 ml) and 1M KH2PO4 (400 ml). The ether layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure to yield methyl 4-cyano-4-(4-nitrophenyl)hexanoate (14.1 g, 99%) as an orange oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH:10]([OH:12])[CH3:11]>CC#N>[CH3:11][CH:10]([OH:12])[CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(O)CCCl
Reactant: C1COCCN1
Solvent: CC#N
Product: CC(O)CCN1CCOCC1

Procedure:
To 100 mL of CH3CN is added morpholine (9.6 g, 0.11 mol) and 4-chloro-2-butanol (11 g, 0.1 mol). Heat the reaction at reflux and monitor the reaction by thin-layer chromatography. Upon completion of the reaction remove the solvent and add saturated aqueous sodium bicarbonate and ether. Separate the layers and dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Agent: Cl
Product: CCCS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F
Reaction time: 2 h
Yield: 88 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)propan-1-sulfonamide (20 mg, 0.038 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)propan-1-sulfonamide (percentage yield: 88%), was obtained.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:19][CH2:20][CH2:21][N:22]([CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]/[CH:41]=[CH:42]\[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCC/C=C\CCCCCCCCOCCN(CCOCCCCCCCC/C=C\CCCCCCCC)CCC(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
The resulting ethyl 3-(bis(2-((Z)-octadec-9-enyloxy)ethyl)amino)propanoate (200 mg, 0.283 mmol) was dissolved in ethanol (4 mL), and stirred at room temperature for 6 hours after adding a 2 mol/L sodium hydroxide aqueous solution (3 mL). The pH was brought to 6 by adding a 1 mol/L hydrochloric acid aqueous solution to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration to give 3-(bis(2-((Z)-octadec-9-enyloxy)ethyl)amino)propanoic acid (188 mg, 98.0%).
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([Si:14](OC)([O:17][CH3:18])[O:15][CH3:16])[CH2:12][CH3:13]>CCOCC>[CH3:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[Si:14]([CH2:11][CH2:12][CH3:13])([O:17][CH3:18])[O:15][CH3:16]
Reactant: Cc1cccc(C)c1Br
Reactant: CCC[Si](OC)(OC)OC
Agent: [Mg]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A 500 mL round bottomed flask was charged with magnesium powder (2.1 g, 86 mmol, Aldrich) and ether (250 mL, Aldrich). 2-Bromo-m-xylene (9.0 mL, 68 mmol, Aldrich) was added over a 25 minute period. The contents were refluxed overnight (18 hours). The brown solution was cooled to room temperature and propyl-trimethoxysilane (17.8 mL, 101 mmol) was added over 20 minutes. A white precipitate formed. The contents were stirred at room temperature overnight (18 hours). The reaction was poured into 0.2N aqueous HCI (500 mL), the layers were separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (13.5 g crude). Distillation under reduced pressure (b.p. 57° C., 0.04 mm Hg) provided (2,6-dimethylphenyl)-propyl-dimethoxysilane (6.8 g, 28 mmol, 41% yield); C13H22SiO2 (Mw=238.40); 1H NMR (CDCl3) δ7.2 (t, 1H), 7.0 (d, 2H), 3.6 (s, 6H), 2.5 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ145.2, 131.0, 129.6, 128.0, 49.8, 23.4, 17.9, 16.7, 16.3; MS m/z (relative abundance) 238 (8), 195 (100), 165 (22), 133 (12), 119 (10), 105 (13), 91 (9), 59 (16).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.Cl([O-])=[O:32].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][CH2:9][C:10]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[C:14]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[C:12]([OH:32])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(COCc2ccccc2)c(C=O)c(OCOC)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 112.8 %

Procedure:
The above-obtained 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzaldehyde (0.80 g, 2.3 mmol) was dissolved in tert-butyl alcohol (20 mL) and the obtained solution was added with 2-methyl-2-butene (10 mL, 94 mmol), sodium chlorite (2.0 g, 22 mmol), sodium dihydrogen phosphate (2.0 g, 17 mmol) and water (5 mL), followed by stirring at a room temperature for 10 hours. The reaction mixture was extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure to obtain 2-(benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (0.94 g, 100%).
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:14](=[C:15]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH:13]=[CH:12]1)=O)C1C=CC=CC=1>C(O)(C)C.[Pd]>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:15]2[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]3[C:14]=2[CH2:13][CH2:12][NH:11][CH2:20][CH2:19]3)=[CH:25][CH:26]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)C=CN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reaction time: 16 h

Procedure:
A mixture of 3-(4-fluoro-phenyl)-2-isopropyl-7,8-dihydro-2H-1,2,6-triaza-azulene-6-carboxylic acid benzyl ester (0.2 g, 0.49 mmol) and 10% Pd/C (20 mg) in isopropanol (20 mL) was subjected to H2 (45 psi) at rt for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by FCC to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=2)=[O:16])[CH:8]=1)C.O[Li].O>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][C:9]=1[NH:14][C:15]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:18]=1)=[O:16]
Reactant: CCOC(=O)COc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)COc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)cc3ccccc23)c1

Procedure:
Compound 9c was synthesized from 8c (0.23 mmol) and LiOH.H2O (0.71 mmol) using the procedure according to the Method E described above.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)c(F)c1

Procedure:
To a solution of 13.75 g (0.0967 mole) of 2-fluoro-4-methoxyaniline in 120 mL of toluene was slowly added over a period of 30 minutes a solution of 19.13 g (0.0967 mole) of trichloromethyl chloroformate in 30 mL of toluene. During the addition the temperature rose to 35° C. The reaction mixture was stirred without external heating for 30 minutes and then heated at reflux for approximately 17 hours. At the end of this time all of the solvent was removed by distillation, leaving 2-fluoro-4-methoxyphenyl isocyanate as a purple liquid, which was used immediately in Step B.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCOCC1>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 4.80 g (7.11 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 16 ml of 1,4-dioxane, 1.40 g (7.24 mmol) of 5-bromo-2-chloropyrimidine and 1.6 ml (9.4 mmol) of diisopropylethylamine were added, and the reaction solution was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 40 ml of 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 5.09 g of the title compound as a white solid (yield: 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C(O)(=O)C>[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccc(F)cc2)s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCc1ccc(-c2ccc(F)cc2)s1
Reaction time: 24 h

Procedure:
40 mg of 5% palladium on carbon were added to a solution of 500 mg (2.0 mmol) of 3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of tetrahydrofuran, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. 10 ml of methanol and 40 mg of 5% palladium on carbon were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. 10 ml of acetic acid were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.