Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:53].O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([O:51][CH3:53])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
To the solution of acid 104 (1.7 g, 2.35 mmol) in CH2Cl2 (7.8 mL) was added TMSCHN2 (1.4 mL, 2.82 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired methyl ester 105 (560 mg, 32%) as a solid. MH+737.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(OCc3ccccc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
4-(3-Benzyloxy-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (534 mg, 1.4 mmol) from Step 2 was dissolved in CH2Cl2 (5 mL) and treated with trifluoroacetic acid (1.05 mL, 14.1 mmol). After 2 hours, the solution was concentrated to provide the title compound which was used without further purification (550 mg).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[NH2:12])=[O:6])[CH2:2][CH3:3].[C:13](OC)(OC)([O:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[N:12]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[O:18][CH3:19])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccsc1N
Reactant: CCCCC(OC)(OC)OC
Solvent: CO
Product: CCCCC(=Nc1sccc1C(=O)NCCC)OC
Temperature: 130 °C

Procedure:
In a destillation apparatus, a mixture of 1.84 g of 2-aminothiophene-3-carboxylic-acid propylamide and 2.43 g of trimethyl orthovalerate is heated for 2 hours at 130° C. Methanol, which arises during the reaction is directly distilled out of the reaction flask. After cooling, the crude product is purified by column chromatography (eluant:hexane/ethylacetate=1:2). Yield:1.9 g pure 2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide; m.p. 68-70° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29]OS(C)(=O)=O)[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[I-:35].[Na+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][I:35])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](CI)[C@H]1OC(C)=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A suspension of 10 (2.0 g) and sodium iodide (1.0 g) in DMF (15 ml) is heated with stirring for 16 hours at 70° C. (bath temperature). The mixture is evaporated in vacuo to a residue, which is partitioned between chloroform and water. The organic layer is dried and evaporated to a syrup (2.0 g), which is put on a column of silica gel and eluted with CHCl3 --EtOAc (95:5, v/v). The title compound is isolated in 94% yield: m.p. 91°-92° C. (MeOH); [α]D27 +203±0.9° (C 1.06, CHCl3).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:4]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(NCCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: BrCCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.0 g (2.41 mM) of N-[3-(4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.7 ml (12.2 mM) of triethylamine in ethanol (10 ml) was added 0.45 ml (2.96 mM) of 1-bromo-3-phenylpropane at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50-100%) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH:34]=2)O1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=3)=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Br)ccnc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1

Procedure:
Following the procedure described for Intermediate 99 with 4-bromo-2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine and 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate gave the title compound. ESMS [M+H]+: 518.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12](Cl)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(Cl)Cl.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[N:13]=[C:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNc1nc(Cl)nc(Nc2cc(Cl)cc(Cl)c2)n1
Reactant: Nc1ccc(O)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Nc2ccc(O)cc2)nc(Nc2cc(Cl)cc(Cl)c2)n1
Yield: 74 %

Procedure:
The title compound was synthesized from 2-(3,5-dichlorophenylamino)-4-methylamino-6-chloro-1,3,5-triazine and 4-aminophenol using a similar procedure to the one used in 8. Yield: 74%; Tg 83° C., Tc 155° C., Tm 187° C.; FTIR (CH2Cl2/KBr) 3401, 3282, 3180, 3112, 2952, 2918, 2850, 1572, 1514, 1503, 1421, 1400, 1366, 1258, 1227, 1168, 1114, 1080, 1011, 993, 937, 833, 807, 737, 703, 668, 632 cm−1; 1H NMR (300 MHz, DMSO-d6, 298 K): δ 9.43 (br s, 0.5H), 9.29 (br s, 0.5H), 9.00 (br s, 0.5H), 8.83 (br s, 0.5H), 7.90 (br d, 2H), 7.43 (br s, 2H), 7.06 (s, 1H), 7.00 (br s, 1H), 6.70 (d, 3J=8.8 Hz, 2H), 2.81 (d, 3J=4.1 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 165.9, 164.0, 163.6, 152.7, 143.0, 133.6, 131.1, 122.6, 120.0, 117.1, 114.9, 27.2 ppm; HRMS (EI) calcd. for C16H14Cl2N6O (m/e): 376.0606.found: 376.0601.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56]>>[C:55]([C:42]1[CH:43]=[C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:45]=[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:41]=1[O:22][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])([CH3:58])([CH3:57])[CH3:56]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(Br)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C(C)(C)C)c(OC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c(C(C)(C)C)c1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 2-bromo-1,3,5-tri-tert-butyl-benzene. MS: 652.2 [M−H]−.
Reaction SMILES: [CH:1]([C@@H:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7](=[O:37])[NH:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>CN(C=O)C>[CH:1]([C@H:4]1[CH2:5][N:6]([CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]2)[C:7](=[O:37])[N:8]1[C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=4)=[CH:20][CH:19]=3)=[C:11]2[N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a stirred solution of (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, Step 4; 80 mg, 0.15 mmol) in DMF (1 mL) was added NaH (60% dispersion in mineral oil, 12 mg, 0.31 mmol) at 0° C. under N2. After stirring at ambient temperature for 30 minutes, a solution of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (77 mg, 0.28 mmol) in DMF (0.5 mL) was added dropwise. The reaction mixture was heated at 80° C. for 1 hour. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 1:4) to give (S)-tert-butyl 4-((4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate (99 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[C:5]([C:19]#[N:20])=[C:4]([C:21]#[N:22])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH:29](OCC)(OCC)[O:30][CH2:31][CH3:32].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]=[CH:29][O:30][CH2:31][CH3:32])=[C:3]([S:23]([C:25]([F:27])([F:26])[F:28])=[O:24])[C:4]([C:21]#[N:22])=[C:5]1[C:19]#[N:20]
Reactant: N#Cc1c(S(=O)C(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)c(C#N)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 1.17 h

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,3-dicyano-4-trifluoromethylsulfinylpyrrole (290 mg, 0.6 mmol), triethyl orthoformate (4.45 g, 29.7 mmol), and p-toluenesulfonic acid (10 mg, 0.1 mmol) was heated at 100° C. for 40 minutes, then at 120° C. for 70 minutes. Additional p-toluenesulfonic acid (a catalytic amount) was added and the resulting mixture was heated at 120° C. for 2.4 hour. It was then concentrated to dryness and diluted with dichloromethane (20 ml). The organic layer was washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), and concentrated to afford the title compound as an orange oil which was used without purification for the next transformation. 19F-NMR: −64.23, −72.08.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=1)[NH2:28]>>[CH3:24][N:23]([CH3:25])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)[N:28]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=437.2 (M+H)+
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:20])[CH:7]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]([O:10]CC)=[O:9])C.CO>O>[CH3:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][CH:7]([C:8]([OH:10])=[O:9])[C:6]([OH:20])=[O:5]
Reactant: CCOC(=O)C(CCOCCOC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCOCCC(C(=O)O)C(=O)O
Yield: 98 %

Procedure:
Sodium hydroxide (2.00 g, 50.00 mmol) in water (15 mL) was added to a stirred solution of diethyl[2-(2-methoxyethoxy)ethyl]malonate (Step 1) (2.35 g, 8.96 mmol). The reaction was kept at ambient temperature for 10 minutes before MeOH was removed in vacuo. The resulting solution was acidified to pH=1 by the addition of HCl (5 M). Diethyl ether was added and the two phases were separated. The aqueous phase was extracted three times with diethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to give the title compound as a colourless oil (1.81 g), 1H NMR (300 MHz, CDCl3) δ 7.16 (br s, 2H), 3.58 (m, 7H), 3.40 (s, 3H), 2.23 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Product: CN(C)c1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol (2 g, 7.54 mmol, 1.00 equiv) in POCl3 (20 mL). The resulting solution was stirred for 5 h at 140° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of dichloromethane. The resulting mixture was washed with 2×20 mL of saturation sodium bicarbonate solution and 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.0 g (93%) of 4-(4-chloroquinazolin-2-yl)-N,N-dimethylaniline as a red solid. MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([NH2:18])=[C:13]([CH3:19])[CH:12]=1)[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:20]([C:22]([CH3:24])=O)[CH3:21]>[Pt].C1(C)C=CC=CC=1>[CH:20]([NH:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:1]([CH2:2][CH3:3])[CH3:11])=[C:4]([CH3:10])[CH:3]=2)=[CH:12][C:13]=1[CH3:19])([CH2:22][CH3:24])[CH3:21]
Reactant: Cc1cc(Cc2cc(C)c(N)c(C)c2)cc(C)c1N
Reactant: CCC(C)=O
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1c(C)cc(Cc2cc(C)c(NC(C)CC)c(C)c2)cc1C
Temperature: 22 °C
Reaction time: 4.5 h
Yield: 96 %

Procedure:
4,4′-Methylenebis(2,6-dimethylbenzeneamine) (1.25 g), methyl ethyl ketone (15 g), Pt(S)/C (0.10 g), and toluene (40.0 g) were charged into reactor. The reactor was purged 3 times with 110 psig (8.60×105 Pa) of H2 at 22° C. The reaction mixture was then stirred at 22° C. under 110 psig (8.60×105 Pa) of H2 for 4.5 hours. GC (conditions: 100° C./5 minutes/10° C.-minute/270° C.) showed 35% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 4 hours at 60° C., after which GC showed 79.5% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine). The reaction mixture was then stirred for 11 hours at 130° C., after which GC showed 100% conversion of 4,4′-methylenebis(2,6-dimethylbenzeneamine), and a 96% yield of N,N′-di-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine); the remaining 4% was determined to be N-sec-butyl-4,4′-methylenebis(2,6-dimethylbenzeneamine). The product was observed to be water-white in color, and the structure of the product was confirmed by GC-MS.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:1][C:2]2[CH:3]=[C:4]([C:14]3[N:15]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:16]([C:19]4[S:20][CH:21]=[CH:22][N:23]=4)=[CH:17][CH:18]=3)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (117 mg, 0.272 mmol) synthesized in Example (38d) was dissolved in dichloromethane (20 mL), and 4-methoxycarbonylphenyl boronic acid (100 mg, 0.556 mmol), copper (II) acetate (80 mg, 0.440 mmol), triethylamine (0.20 mL, 1.435 mmol) and molecular sieves 4A (100 mg) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. The deposit of this reaction solution was Celite filtered. This mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=15%-25%) to afford the desired compound (70 mg, yield 46%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.Cl[CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Reactant: ClCCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/ethanol=25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]1([F:16])[F:15])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[F:15][C:7]1([F:16])[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]1[CH2:5][OH:4]
Reactant: CC(=O)OC[C@H]1[C@H](c2ccccc2)C1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1[C@H](c2ccccc2)C1(F)F
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
To a solution of trans-1-acetoxymethyl-2,2-difluoro-3-phenylcyclopropane (9.7 mmol, prepare according to Kobayashi et al. J. Org. Chem, 1982, 47, 3232) in methanol (50 mL) was added K2CO3 (1.34 g, 9.7 mmol) and the reaction was stirred for 20 mins. The solution was then decanted from the solids and concentrated. The residue was purified by column chromatography (silica gel, ether:hexanes, 35:65) to afford 1.72 g (96%) of trans-2,2-difluoro-1-hydroxymethyl-3-phenylcyclopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=2)[N:4]=1.O[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:10]=2)[N:6]=[C:5]([NH:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[O:35][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NCc2cccc(O)c2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)nc(NCc2cccc(OCCCNC(=O)OC(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of Example 63A (0.510 g, 1.05 mmol), tert-butyl 3-hydroxypropylcarbamate (0.275 g, 1.57 mmol) and triphenylphosphine (0.412 g, 1.57 mmol) in tetrahydrofuran (13 ml) was added dropwise diisopropyl azodicarboxylate (DIAD) (0.305 ml, 1.57 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. Flash chromatography isolation (gradient elution, ethyl acetate/hexane 0-50%) gave the title compound.