Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:37][C:38]1[C:39]([C:46]([NH:48][C:49](=[NH:52])SC)=[O:47])=[N:40][C:41]([Cl:45])=[C:42]([NH2:44])[N:43]=1>C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:15]([CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([NH2:52])=[N:48][C:46]([C:39]2[C:38]([NH2:37])=[N:43][C:42]([NH2:44])=[C:41]([Cl:45])[N:40]=2)=[O:47])=[CH:7][CH:8]=1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(=O)O
Temperature: 65 °C
Yield: 74.7 %

Procedure:
The compound 280 (0.077 g, 0.211 mmol) was mixed with ethanol (5 mL). The mixture was heated at 65° C. for 15 min to achieve complete dissolution. To the clear solution were sequentially added diisopropylethylamine (0.184 mL, 1.056 mmol) and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.99 g, 0.254 mmol). The mixture was heated at 65° C. for an additional three hours. It was then concentrated under vacuum. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-2.2%), methanol (0-22%) and dichloromethane (100-75.8%) to afford the product 290 (0.091 g, 75%) as a yellow solid. 1H NMR (300 MHz, CD6OD): δ 1.44 (s, 9H), 1.58-1.84 (m, 8H), 2.54-2.68 (m, 4H), 3.34-3.42 (m, 2H), 4.02 (m, 1H), 7.08 (s, 4H). m/z (APCI) 577 [C26H37ClN8O5+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32](B(O)O)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=5[CH3:35])[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(C)c(B(O)O)cn1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(C)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)cn1
Temperature: 120 °C
Yield: 63.9 %

Procedure:
To a mixture of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (25 mg, 0.067 mmol) and 2-methoxy-4-methylpyridin-5-ylboronic acid (21 mg, 0.1 mmol) in DME (0.7 mL) and Na2CO3 (2M, 0.065 mL, 0.13 mmol) was added Pd(PPh3)4 (4 mg, 0.003 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The reaction was re-partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (20 mg, 65%). 1H NMR (400 MHz, CDCl3) 8.05 (s, 1H), 7.86 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.21-7.16 (m, 2H), 7.04 (d, J=8.2 Hz, 1H), 6.62 (s, 1H), 3.92 (s, 3H), 2.34 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.74 (dd, J=3.9, 6.9 Hz, 2H), 1.15 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 2.00 min; ESI-MS m/z calc. 467.5. found 468.2 (M+H)+.
Reaction SMILES: [ClH:1].C1(C[N:9]2[CH2:14][CH2:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])([CH3:15])[CH2:11][CH2:10]2)C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[CH3:15][C:12]1([NH:16][C:17](=[O:19])[CH3:18])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)NC1(C)CCNCC1
Yield: 91.2 %

Procedure:
A solution of 19 g of N-[1-(phenylmethyl)-4-methyl-4-piperidinyl]acetamide hydrochloride in 400 ml of methanol was hydrogenated at normal pressure and at room temperature with 5 g of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 11.8 g of N-[4-methyl-4-piperidinyl]acetamide hydrochloride; mp. 230°-233° C. (interm. 3).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=3[CH:18]=2)[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>CO>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)[CH:9]=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: COC(=O)C1(c2ccc3c(c2)C(C)(C)CO3)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COc2ccc(C3(C(=O)O)CC3)cc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 mL) was added LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40° C. overnight. HCl (10%) was added slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (10 mL×3). The extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by preparative HPLC to give 1-(3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g, 41%). 1H NMR (400 MHz, CDCl3) δ 7.11-7.07 (m, 2 H), 6.71 (d, J=8 Hz, 1 H), 4.23 (s, 2 H), 1.66-1.63 (m, 2 H), 1.32 (s, 6 H), 1.26-1.23 (m, 2 H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br)=[O:12])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])=[C:15]([CH2:21][N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:16]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1CN1C(=O)c2ccccc2C1=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
Compound 1-3 (6.0 g 0.015 moles) was dissolved in 50 mL of DMF. To that pthalimide (3.31 g 0.023 moles), K2CO3 (6.2 g 0.045 moles) and a catalytic amount of KI were added and allowed to stir at 50° C. overnight. Upon completion the reaction was diluted with ethyl acetate and then washed with brine (6×25 mL's) to afford 2.9 grams of 1-4 in a crude mixture, which was then purified by normal phase chromatography. 1H NMR (300 MHz, CDCl3): 4.83 ppm (2H, S); 7.05 ppm (2H, m); 7.36 ppm (1H, dd, J=2.4 Hz, 8.6 Hz); 7.50 ppm (1H, dt, J=1.5 Hz, 8.5 Hz); 7.59 ppm (1H, d, J=2.4 Hz); 7.75 ppm (3H, m); 7.91 ppm (2H, m); 8.18 ppm (1H, d, 7.2 Hz); 10.17 ppm (1H, s); 12.27 ppm (1H,s) Analytical LCMS: single peak (214 nm) at 3.633 min (CH3CN/H2O/1% TFA, 4 min gradient), HRMS calc'd for C22H15N2O4Cl (M+H), 407.0799; found 407.0793 (M+H).
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[N+:14]=[N-:15])[C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(=[N+]=[N-])c1ccc(Cl)cc1
Yield: 83.2 %

Procedure:
A solution of 4-acetamidobenzenesulfonyl azide (1.43 g, 5.96 mmol) and methyl 2-(4-chlorophenyl)acetate (1 g, 5.42 mmol) in acetonitrile (27 mL) was cooled to 0° C. DBU (0.907 g, 0.891 mL, 5.96 mmol) was then added dropwise to the reaction mixture. The mixture was allowed to stir over night, after which it was passed through a plug of silica and purified by column chromatography (EtOAc) to give methyl 2-(4-chlorophenyl)-2-diazoacetate (0.95 g, 83%) as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](Br)=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:40]3[CH:39]=[N:38][C:37]([CH3:36])=[N:42][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Cc1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-methyl-5-bromopyrimidine following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.221 min, m/z=468.2; 1H NMR (CDCl3) 1.06 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.11-2.28 (m, 4H), 2.31-2.42 (m, 1H), 2.70 (s, 3H), 2.82 (m, 1H), 5.65 (m, 1H), 7.00 (d, 2H), 7.21-7.34 (m, 7H), 8.19 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:3][CH:2]=1.[CH2:14]=[O:15]>>[OH:15][CH2:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:8]=1
Reactant: O=c1ccc(-c2ccncc2)c[nH]1
Reactant: C=O
Product: O=c1[nH]cc(-c2ccncc2)cc1CO

Procedure:
The reaction of 5-(4-pyridinyl)-2(1H)-pyridinone with excess formaldehyde at an acidic pH to produce 3-hydroxymethyl-5-(4-pyridinyl)-2(1H)-pyridinone is carried out by heating the reactants at about 75° to 125° C. It is preferably run using an acidic pH of about 2.0 to 5.0, a large molar excess of formaldehyde and a reaction temperature of about 90° to 110° C. The quantity of formaldehyde can vary widely provided it is in excess of said 5-(4-pyridinyl)-2(1H)-pyridinone. In practice, a large excess, e.g., from about 10-fold to 100-fold or greater can be used; however, as little as a 2-fold excess or less of formaldehyde can be used although the reaction time is longer. Because of its ready availability and low cost, 37% aqueous formaldehyde solution is preferred.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(C)=O)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 5, using the following starting materials: (3-{2-[(acetyl-ethyl-amino)-methyl]-4-amino-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester and 4-chlorobenzoyl chloride.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:12])[CH3:9].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42]>ClCCl>[CH2:8]([O:10][C:11]([C:13]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[CH2:17][CH2:16][N:15]([C:41](=[O:42])[NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[Cl:33])[CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Reactant: O=C=Nc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccccc2Cl)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
Triethylamine (0.23 mL, 1.67 mmol) was added to a stirred solution of 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 65) (185 mg, 0.54 mmol) in dichloromethane (10 mL) and the resulting mixture cooled to 0° C. 2-Chloro phenyl isocyanate (0.065 mL, 0.54 mmol) was added and the reaction mixture stirred at room temperature for 16 hours. The mixture was partitioned between water (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed brine (25 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 25% ethyl acetate in hexane to afford the title compound as a colourless liquid (245 mg, 91%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[N:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14][CH3:15])=[O:6])[CH2:2][CH3:3].[Cl:20]N1C(=O)CCC1=O>N1C=CC=CC=1>[CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[C:10]([Cl:20])[S:9][C:8]=1[N:12]=[C:13]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14][CH3:15])=[O:6])[CH2:2][CH3:3]
Reactant: CCCCC(=Nc1sccc1C(=O)NCCC)OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: CCCCC(=Nc1sc(Cl)cc1C(=O)NCCC)OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a sulfonation flask 0.85 g 2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide are added with stirring to 10 ml absolute pyridine. The internal temperature is then raised to 60° C. and 0.5 g of N-chlorosuccinimide (NCS) are added in two portions. After stirring for 1 hour at 60° C., the pyridine is removed in a water jet vacuum. The residue is taken up in ethylacetate and the organic phase is washed twice with water. After drylng of the organic phase, the solvent is removed in a water jet vacuum and the raw material purified by column chromatography over silica gel (eluant:hexane/ethylacetate=3:1). Yield: 0.6 g 5-Chloro-2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide in the form of brownish crystalls; m.p. 110-112° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[C:7]([CH3:24])=[C:8]([N:13]3[C:21](=O)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=O)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1>C(O)C>[CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[C:7]([CH3:24])=[C:8]([N:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:21]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2
Solvent: CCO
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2
Yield: 84 %

Procedure:
By using 2-[2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 84%. Melting point: 161-163° C. (Ethanol)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14](=O)[CH3:15]>CN(C=O)C>[CH3:15][C:14]1[N:11]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[S:10][CH:13]=1
Reactant: NC(=S)Nc1cccc(O)c1
Reactant: CC(=O)CBr
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cccc(O)c2)n1
Yield: 61 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 3-hydroxyphenylthiourea (100 mg, 0.59 mmol) and bromoacetone (98 mg, 0.71 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 61% yield (74 mg).
Reaction SMILES: CC1(C)COB([C:8]2[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]3([CH3:26])[C:20]([F:22])([F:21])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]3)[CH:13]=2)OC1.Cl[C:31]1[O:32][C:33]2[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=2[N:35]=1>[Pd]>[F:41][C:37]1[C:38]([F:40])=[CH:39][C:33]2[O:32][C:31]([C:8]3[C:9]([F:28])=[CH:10][C:11]([F:27])=[C:12]([C@:14]4([CH3:26])[C:20]([F:21])([F:22])[C:19]([CH3:24])([CH3:23])[O:18][CH2:17][C:16](=[O:25])[NH:15]4)[CH:13]=3)=[N:35][C:34]=2[CH:36]=1
Reactant: CC1(C)COB(c2cc([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c(F)cc2F)OC1
Reactant: Fc1cc2nc(Cl)oc2cc1F
Agent: [Pd]
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(F)c(F)cc4o3)c(F)cc2F)C1(F)F
Yield: 74 %

Procedure:
In a manner analogous to that described in Example 19a), the palladium-catalyzed coupling of (R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (intermediate D1.1) and 2-chloro-5,6-difluorobenzo[d]oxazole yielded the title compound (74% yield) as a white powder. MS (ISP): m/z=459.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.C1C(=O)N([Br:19])C(=O)C1>CC(N=NC(C#N)(C)C)(C#N)C.ClC1C=CC=CC=1>[CH3:1][Si:2]([CH3:10])([CH3:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc([Si](C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: C[Si](C)(C)c1cccc(CBr)c1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A mixture of m-trimethylsilyltoluene (8.22 g, 50 mmol), NBS (8.90 g, 50 mmol), AIBN (0.05 g) and chlorobenzene (50 ml) was heated by means of a heating bath preheated to 110° C. An exothermic reaction started when the reaction mixture reached 80-90° C. and the orange suspension became a colorless solution within minutes. The mixture was cooled down with the aid of an ice-bath, ice water was added and the resulting mixture was extracted with hexane. The organic phase was washed with water, then brine and dried (MgSO4). Filtration through a silica plug (10 g) followed by evaporation of solvents yielded 12.05 g (99%) of 37 as a colorless liquid. Spectroscopic data were identical to those reported in the literature.43
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH:19]=[CH2:20])[C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OC)(C)(C)C.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:12]=3[O:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCc1c(O)ccc2c(CCc3ccccc3)coc12
Agent: [Pd]
Solvent: COC(C)(C)C
Product: CCCc1c(O)ccc2c(CCc3ccccc3)coc12
Reaction time: 0.5 h

Procedure:
The product from Step E (1.116 grams) was dissolved in methyl tert-butyl ether (12 mL) and placed in a hydrogenation bottle. 5% Pd/C catalyst (110 mg) was added and the mixture hydrogenated for 0.5 hour using a Parr apparatus (14 psi). Filtration through Celite and evaporation gave the title compound as a yellow oil. On standing, a pale yellow solid formed which required no additional purification.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:19][CH2:20][NH:21][S:22]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)(=[O:24])=[O:23])[C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[S:22]([NH:21][CH2:20][CH2:19][N:6]([C:7](=[O:18])[CH2:8][N:9]1[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH2:5][C:4]([OH:34])=[O:3])(=[O:23])=[O:24]
Reactant: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2nc3ccccc3s2)CC(=O)O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
N-[2-(Benzothiazole-2-sulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine ethyl ester (5.10 g, 10 mmol) was suspended in tetrahydrofuran (20 mL) and the solution of lithium hydroxide monohydrate (1.03 g, 25 mmol) in water (20 mL) was added. The reaction mixture was stirred for 1 h. at ambient temperature. The aqueous solution was acidified by the dropwise addition of 1N HCl at 0° C. The title compound was extracted with ethyl acetate (3×10 mL), the combined extracts were dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness in vacuo to afford the desired product (4.57 g, 95%). 1H NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.28 (s, 0.4H), 8.88 (s, 0.6H), 8.77 (s, 0.4H), 8.27 (d, 1H), 8.18 (d, 1H), 7.69˜7.64 (m, 2H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.64 (s, 1.2H), 4.45 (s, 0.8H), 4.21 (s, 0.8H), 3.98 (s, 1.2H), 3.52 (t, 1.2H), 3.38 (s, 2H), 3.21 (t, 0.8H), 1.73 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([N:12]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:24][CH:23]=1)C(=O)OC(C)(C)C)(=[O:11])=[O:10].[OH-].[Na+]>ClCCl>[CH3:33][C:31]1([CH3:34])[C:30]([CH3:35])([CH3:36])[O:29][B:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][NH:12][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:27][CH:26]=2)[O:32]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OB(c2ccc(CCNS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a 0° C. solution of tert-butyl (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (from the previous step, assumed 19.7 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0° C. and brought to pH 10.5 with a 4N aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to provide the title compound as an off-white solid. Yield: 2.5 g, 7.7 mmol, 39% over two steps. LCMS m/z 326.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 12H), 2.84 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 3.42 (dt, J=6.6, 6.6 Hz, 2H), 4.18 (br t, J=6 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15]>>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH:6]=[N:12][NH:13][C:14]([NH2:16])=[S:15]
Reactant: NNC(N)=S
Reactant: Cc1ccccc1C=CC=O
Product: Cc1ccccc1C=CC=NNC(N)=S
Yield: 42 %

Procedure:
The compound is prepared according to the method described in Example 1A from 2-methylcinnamaldehyde (0.27 mmol) and from thiosemicarbazide (0.27 mmol). Yield 42%.