Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.OS(O)(=O)=O.[CH3:30]CN(CC)CC>CO>[CH3:30][O:1][C:2]1([CH3:24])[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: CC1(O)OC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC1(C)OC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution of 5-hydroxy-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone (Example 4) (1.0 g) in 120 mL of MeOH was added 0.1 mL of concentrated H2SO4. The mixture was heated to reflux for 3 days and then treated with 2 mL of Et3N. Methanol was removed under reduced pressure and the residue was purified by silica gel flash chromatography eluted with 4:1 toluene/EtOAc. After a swish from 2:1 hexane/EtOAc, 0.8 g of the title compound was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH:14][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(N)c1sc2ccccc2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1sc2ccccc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(3-phenylbenzo[b]thiophen-2-yl)ethylamine from Example 23 (160 mg, 0.63 mmol), 6-chloro-9H-purine (98 mg, 0.63 mmol) and DIPEA (0.16 mL, 0.95 mmol) in n-butanol (1.3 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) and then triturated with EtOAc affording 101 (105 mg, 45%). LCMS: RT 4.33 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.16-8.10 (2H, m), 7.92-7.86 (1H, m), 7.66-7.54 (4H, m), 7.50-7.44 (1H, m), 7.37-7.26 (3H, m), 5.76 (1H, s), 1.50 (3H, d, J=6.94 Hz)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:31](O)([C:33]([F:36])(F)F)=O>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:11][C:14]4[CH:23]=[CH:31][C:33]([F:36])=[CH:16][CH:15]=4)=[O:7])[CH2:13][CH2:12]3)=[CH:15][C:16]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCCCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(n-pentylamino)quinoline (68 mg, 0.11 mmol) is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (18 μL, 0.16 mmol) and triethylamine (110 μL, 0.79 mmol) to give a colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>>[Cl:8][C:9]1[N:10]=[C:11]([NH:1][C@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4])[CH:12]=[N:13][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)[C@@H](N)CO
Product: CC(C)[C@H](CO)Nc1cncc(Cl)n1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-20 and A-3 [C]: i) (R)-2-amino-3-methyl-butan-1-ol has been reacted with 2,6-dichloropyrazine to give (R)-2-(6-chloro-pyrazin-2-ylamino)-3-methyl-butan-1-ol; ii) subsequent condensation with 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) gave the title compound as a light yellow solid. MS: 341.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.CO>[OH-].[K+].CCO.C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:21](=[CH:32][C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19]3)[N:10]=[CH:9]1
Reactant: O=Cc1cccs1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: O=C1C(=Cc2cccs2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 43.9 %

Procedure:
According to the method of Example 32, Step 2, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.356 g, 1.0 mmol) was reacted with thiophene-2-carboxaldehyde (0.174 g, 1.55 mmol) in 5 mL of 4% KOH in EtOH for 24 hours to afford, after chromatography (silica gel, 60 g; 8% MeOH in DCM), 0.154 g (40%) of the title compound as a red glassy solid, mp 60-63° C.: CI-MS m/e 351 (M+ +1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CN(C)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide (0.15 g, 0.35 mmol) in DCM (16 mL) and methanol (8 mL) was added formaldehyde (0.053 mL, 37% aq., 0.7 mmol), sodium triacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL, 0.42 mmol). The reaction mixture was stirred at RT for 16 h. Sodium hydrogen carbonate (aq.) and 10% Methanol in DCM were added to the mixture and the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 414 (94 mg, 62%). LCMS: RT=2.31 min, [M+H]+=434. 1H NMR 400 MHz (DMSO-d6) δ: 8.32 (1 H, d, J=8.35 Hz), 7.92 (1 H, s), 7.91 (1 H, d, J=0.62 Hz), 7.11 (1 H, br, s), 7.08 (1 H, dd, J=8.37, 1.83 Hz), 7.02 (1 H, br, s), 6.98 (1 H, d, J=1.79 Hz), 5.94-5.86 (1 H, m), 4.53-4.46 (4 H, m), 3.15 (2 H, s), 2.61 (2 H, s), 2.46 (2 H, s), 2.35 (3 H, s), 1.48 (6 H, d, J=6.60 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH:31]=O>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:29]=[C:30](/[CH:31]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:33]=[CH:34][C:35]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1-c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccc(-c2ccccn2)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethyl(triphenylphosphoranylidene)acetate (550 mg, 1.6 mmol) and 3-methoxy-4-pyridin-2-ylbenzaldehyde (225 mg, 1.1 mmol) were dissolved in CH2Cl2 (5 mL) and stirred at rt for 12 h. The reaction mixture was concentrated and purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 2:3) to afford the desired ethyl(2E)-3-(3-methoxy-4-pyridin-2-ylphenyl)prop-2-enoate.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[N:41]=[N:42][C:43]([Cl:46])=[CH:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:46][C:43]1[N:42]=[N:41][C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[CH:45][CH:44]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)nn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 50.8 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.51 mmol) was reacted with 3-amino-6-chloro-pyridazine (Alfa) (0.15 g, 1.2 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 48 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (6-chloro-pyridazin-3-yl)-amide as a yellow solid (0.15 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][CH2:27][CH:21]2[CH2:22][N:23]([C:28]([O:30]C(C)(C)C)=O)[CH2:24]3)[NH:12][C:11]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[N:10]1.F[C:41](F)(F)C(O)=O>ClCCl>[C:28]([N:23]1[CH2:24][CH:25]2[N:20]([CH2:19][C:13]3[NH:12][C:11]([C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[N:10][C@@H:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Cl:1])[C:14]=3[C:15]([O:17][CH3:18])=[O:16])[CH:21]([CH2:27][CH2:26]2)[CH2:22]1)(=[O:30])[CH3:41]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C1=C(CN2C3CCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3CCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (80 mg), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL) was stirred at room temperature for one hour, and then concentrated. The residue was dissolved in dichloromethane (5.0 mL), followed by adding diisopropylethylamine (0.2 mL) and acetic chloride (0.1 mL). The result mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by prep-HPLC to give Methyl (4R)-6-[(3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 122 (11.3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 251c (1.14 g, 3.10 mmol), methylene chloride (10 mL) and trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 2 h. After this time, the mixture was concentrated under reduced pressure. The resulting residue was diluted with methylene chloride (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford a 92% yield (1.10 g) of 251d as a colorless oil. This compound was used directly for the next step without any purification: 1H NMR (500 MHz, DMSO-d6) d 8.65 (s, 1H), 8.55 (d, 1H, J=2.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.48 (d, 1H, J=2.5 Hz), 7.30 (d, 1H, J=9.0 Hz), 7.21 (m, 1H), 4.95 (t, 1H, J=6.0 Hz), 3.76 (m, 1H), 3.48 (m, 5H); MS (ESI+) m/z 353.0 (M+H).
Reaction SMILES: [N:1]1([C:8]2[C:13]([CH2:14][NH:15][C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])[CH:19]=[N:18][N:17]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C)C=O>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:19]=[N:18][N:17]=[C:16]1[NH:15][CH2:14][C:13]1[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([CH2:36][C:37]([NH2:39])=[O:38])[CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc(-n2cnnc2NCc2cccnc2N2CCCNCC2)c1Cl
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CN1CCCN(c2ncccc2CNc2nncn2-c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a solution of Example 113A (250 mg, 0.597 mmol) in dimethylformamide (7 ml) was added potassium carbonate (165 mg, 1.194 mmol) and bromoacetamide (124 mg, 0.896 mmol). The reaction mixture was stirred at room temperature for 16 hours then poured onto ice water. The aqueous mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) to give the title compound (109 mg). MS (ESI+) m/z 475.6 (M+H)+; Rt=1.41. 1H NMR (DMSO-d6) δ 8,170 (s, 1H); 8,054 (d,1H); 7,832 (d,1H); 7,579(m,3H); 7,251 (s,1H); 7,112 (s,1H); 6,832 (dd,1H); 6,545 (t,1H); 4,338 (d, 2H); 3,423 (m,4H); 3,011 (s,2H); 2,772 (m,2H); 2,710 (m,2H); 1,856(m,2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])/[CH:12]=C/C(OC)=O)(=[O:7])=[O:6].O=O.[O:30]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:27])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:12]=[O:30])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)O[Si](C)(C)C(C)(C)C
Yield: 52 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, methyl (2E)(4S)-6-[(3-chloropropyl)sulfonyloxy]-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (15a) (2.4 g, 5.4 mmol) dissolved in 25 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.59 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:3) as eluent to provide 1.1 g (52% yield) of the title compound (15b) as a colorless oil. Rf=0.75 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.07 (s, 3H), 0.10 (s, 3H), 0.96 (s, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 2.30-2.37 (m, 2H), 3.28-3.32 (m, 2H), 3.69-3.73 (m, 3H), 4.01 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 9.62 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 409.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].N[C:10](N)=[O:11]>>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:10]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: NC(N)=O
Product: O=c1[nH]c2ccccc2[nH]1
Temperature: 170 °C
Yield: 87.6 %

Procedure:
A mixture of o-phenylenediamine (15.0 g) and urea (50.0 g) was heated at a temperature of 170° C. for a period of 45 min. The solid product was washed with water and recrystallised from ethanol to give benzimidazolin-2-one (16.3 g) as colourless crystals, mp>260° C.
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClCCCl.ClC(OC(Cl)C)=O>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:26][CH2:25]3)[C:12](=[O:24])[NH:13][C:14]2=[O:23])=[CH:17][CH:18]=1
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: O=C1NC(=O)C2(CCNCC2)N1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Combine 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (10 mmol) and 1,2-dichloroethane (70 mL). Cool using an ice bath. Add in dropwise fashion, 1-chloroethyl chloroformate (48.6 mmol). Warm to ambient temperature and maintain for 1 h. Extract using saturated NaHCO3 (120 mL). Extract the aqueous phase using dichloromethane (120 mL). Combine the organic layers, extract with saturated NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Add anhydrous methanol (70 mL) and heat at reflux for 1 h. Concentrate in vacuo to obtain a residue and purify to obtain the title compound.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CO>[C:6]([O:8][CH2:9][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:12])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)c1ccc(C(=O)OCCCCCCCCCCCCCCCCCCCCCC)cc1
Temperature: 160 °C
Yield: 98.3 %

Procedure:
To a 3 neck 500 mL round bottomed flask equipped with a Dean Stark trap and condenser, thermocouple and argon inlet was added dimethyl terephthalate (49.57 grams, available from Sigma Aldrich), 1-docosanol (167.76 grams, available from Spectrum Chemical), Fascat 4100 (0.22 grams, available from Arkema Inc) and Xylenes (100 mL, available from Sigma Aldrich). The mixture was slowly heated under argon to 160° C. during which reagents melted. The temperature was raised to 180° C. The reaction mixture was stirred at 180° C. overnight (about 20 hours) during which 63 mL of a mixture of xylenes and methanol was collected. A vacuum was applied (1-2 mm-Hg) for ˜10 minutes during which all the Xylenes were distilled off. The solution was cooled under argon to about 140° C. and discharged in an aluminum tray where it was allowed to cool to room temperature to give 196.6 grams of product as an off-white solid (98% yield). The product was shown to be pure by 1H NMR spectroscopy with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][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(Cl)Cl>[CH3:1][NH:2][C:3]([NH: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:4]
Reactant: Nc1cnc2ccccc2c1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Nc1cnc2ccccc2c1

Procedure:
0.99 ml of methyl isocyanate is added to a solution of 2.0 g of 3-aminoquinoline in 15 ml of methylene chloride under argon and the mixture is heated under reflux for 2 h. A further 0.95 ml of methyl isocyanate is added and the reaction mixture is refluxed again for 2 h. The crude product is chromatographed over 100 g of silica gel (mobile phase gradient from L to P). This gives the title compound as a crystalline solid: Rf (L)=0.2; M+=201.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:21])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To the suspension of 2-nitrobenzoic acid (200 g) and a catalytic amount of dimethylformamide (DMF; 5 mL) in DCM (2.5 L) was added oxalyl dichloride (304 g) dropwise at room temperature over a 30 minute interval. After the addition, the reaction was continued stirring for approximately 1 hour at room temperature and the suspension turned into a clear solution. The completion of the reaction was monitored by TLC (generally ˜1 hour). The reaction mixture was then concentrated at 35° C. to dryness to give 225 g of the crude product (13) as light yellow oil or solid (mp: 17° C., lit), which was directly used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[OH:11]>C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(O)c1
Reaction time: 6 h

Procedure:
A solution of 2-chloro-5-nitrophenol (114 g, 0.66 mol) in ethyl acetate (500 mL) was treated with 5% Pt/C (510 mg, 0.5 weight %) and the mixture shaken under a hydrogen atmosphere (30 psi) for 6 h. The mixture was filtered through Celite® and the residue washed well with ethyl acetate. Evaporation of the ethyl acetate gave a solid (95 g, 100% crude yield) which was taken directly into the next step.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[F:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccccc1F

Procedure:
Benzyl alcohol (2.60 mL, 25.1 mmol) was added slowly to a stirring solution of 2-fluorobenzoic acid (2.92 g, 20.8 mmol), 4-(dimethylamino)pyridine (251 mg, 2.05 mmol), and 1,3-dicyclohexylcarbodiimide (5.16 g, 25.0 mmol) in anhydrous CH2Cl2 at room temperature under an Ar atmosphere. After 18 h the precipitate was filtered off and washed with CH2Cl2, and the filtrate was concentrated with silica to a powder. Flash chromatographic purification over silica (10% to 20% gradient EtOAc in hexanes) afforded 16 as a clear, colorless liquid (4.20 g, 88%). 1H-NMR (500 MHz, CDCl3) δ 5.39 (s, 2H), 7.14 (ddd, J=1.1, 8.4, 9.5 Hz, 1H), 7.20 (dt, J=1.1, 7.7 Hz, 1H), 7.31-7.36 (m, 1H), 7.37-7.41 (m, 2H), 7.44-7.48 (m, 2H), 7.49-7.55 (m, 1H), 7.96 (dt, J=1.8, 7.3 Hz); 13C-NMR (125 MHz, CDCl3) δ 66.93, 117.0 (d, JC-F=22.1 Hz), 118.7 (d, JC-F=9.6 Hz), 124.0 (d, JC-F=3.8 Hz), 128.1, 128.2, 128.6, 132.2, 134.6 (d, JC-F=9.6 Hz), 135.7, 162.1 (d, JC-F=260 Hz), 164.2 (d, JC-F=3.8 Hz); GC-MS 230 m/z [M]+, C14H11OF2 requires 230.