Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:22][C@@H:23]1[O:25][CH2:24]1)(=O)=O>>[CH2:22]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[C:1]#[N:2])[C@@H:23]1[O:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)CCCc1ccc(O)c(C#N)c1
Product: CCOC(=O)CCCc1ccc(OC[C@H]2CO2)c(C#N)c1
Yield: 66.3 %

Procedure:
Using the method of example 30(b), supra, ethyl 4-(3-cyano-4-hydroxyphenyl)butanoate (0.93 g, 4 mmol) and (R)-glycidyl nosylate (1.00 g, 3.86 mmol) were used to prepare 0.74 g (66%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][C:44]([CH2:55][O:56][Si:57]([CH:64]([CH3:66])[CH3:65])([CH:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])=[C:45]([CH:54]=2)[O:46][CH2:47][CH2:48]OS(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:67][NH:68][CH3:69]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[CH:43][C:44]([CH2:55][O:56][Si:57]([CH:58]([CH3:59])[CH3:60])([CH:64]([CH3:65])[CH3:66])[CH:61]([CH3:63])[CH3:62])=[C:45]([O:46][CH2:47][CH2:48][N:68]([CH3:69])[CH3:67])[CH:54]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCOS(C)(=O)=O)(C(C)C)C(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1OCCN(C)C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 55fB (100 mg, 0.11 mmol) and dimethylamine (2.0M in THF, 0.80 mL, 1.60 mmol) in THF (3 mL) was stirred at 60° C. for 18 h in a sealed vial. The volatiles were concentrated in vacuo and the residue was used in the next step without further purification (94 mg, 100%). LCMS (Method 3): Rt 3.75 min, m/z 893 [MH+].
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[SH:7])(=[O:3])[CH3:2].[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[S:7][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 29.2 %

Procedure:
A pyridine solution (100 ml) of 35 g (0.096 mole) of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose [Methods in Carbohydrate Chemistry, Vol. 2, 436 (1963)] and 28 g (0.10 mole) of triphenylmethyl chloride was stirred at room temperature for 12 hours. The solution was filtered and the pyridine removed at reduced pressure. The residue was dissolved in chloroform (350 ml), washed with water (5 × 100 ml) and the chloroform solution dried in magnesium sulfate. The solvent was removed at reduced pressure and the residue dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio-β-D-glucopyranose, m.p. 177°-179°; [α]D25 (1% methanol) = -37.8°.
Reaction SMILES: F[C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].[CH3:21]C1C=C(C=CC=1[N+]([O-])=O)C(O)=O>>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[CH:2][C:17]=1[CH3:21]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1N

Procedure:
The following intermediate was prepared in a manner analogous to Intermediate 62 utilising 3-Methyl-4-nitrobenzoic acid, available form Aldrich, as the starting Nitro acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][OH:41].C([O-])(O)=O.[Na+]>>[OH:41][N:40]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][C@@H:10]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][C@@H:33]([CH3:37])[C:34]([OH:36])=[O:35])=[O:31])=[CH:28][CH:29]=2)=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@@H](C)C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(-c3ccc(C(=O)N[C@@H](C)C(=O)O)cc3)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from (S)-2-({4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carbonyl}-amino)-propionic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white solid, MS (ESI+): m/z=522.3 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28]CNC[CH2:24]2)=[CH:19][CH:18]=1)[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:24][CH2:1][N:2]([CH2:4][C:5]3[C:13]4[C:8](=[N:9][CH:10]=[CH:11][CH:12]=4)[NH:7][CH:6]=3)[CH2:3][CH2:28]2)=[CH:19][CH:18]=1)[CH3:15]
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: CCOc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine [prepared by the method of M. M. Robinson and B. L. Robinson, J. Am. Chem. Soc., 1955, 77, 457] (0.40 g, 2.28 mmol) and 1-(4-ethoxyphenyl)piperazine (0.495 g, 2.40 mmol) in toluene (10 ml) was heated at reflux under nitrogen for 7 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from methanol afforded the title compound (0.513 g, 67%), m.p. 179°-180° C.; (Found: C, 71.27; H, 7.19; N, 16.59. C20H24N4O requires C, 71.40; H, 7.19; N, 16.65%); δH (DMSO-d6) 1.27 (3H, t, J 7.0 Hz, ArOCH2CH3), 2.52 (4H, m, 2×piperazinyl CH2), 2.98 (4H, m, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 3.92 (2H, q, J 7.0 Hz, ArOCH2CH3), 6.80 (4H, m, ArH), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.3 Hz, 4-H), 8.19 (1H, dd, J 4.6, 1.3 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH2:34]([N:37]([CH2:38][CH2:39][CH3:40])[C:18]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH2:35][CH3:36]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: CCCNCCC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Yield: 76.2 %

Procedure:
Operations are carried out as for Example 7, starting from 1.42 g of 1-(2-chlorophenyl) isoquinoline 3-carboxylic acid, 0.58 g of triethylamine, 0.62 g of ethyl chloroformate and 0.66 g of N-propyl propylamine in 50 ml of chloroform. 1.40 g of N,N-dipropyl 1-(2-chloro phenyl) isoquinoline 3-carboxamide, melting at 101° C., are obtained.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[CH:5]1.CI.[C:24](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[OH:1][CH:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:24])=[O:14])[C:7]=2[CH:6]=[CH:5]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cccc2c1ccn2CC(O)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cccc2c1ccn2CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
There were dissolved, in 80 ml of dimethylformamide, 5.39 g of 1-(2-hydroxy-2-phenylethyl)indole-4-carboxylic acid prepared in Example 319 and 3.05 g of methyl iodide, followed by further addition of 2.91 g of potassium carbonate and stirring at room temperature for 30 minutes. The reaction system was poured into 300 ml of a 10% ammonium chloride aqueous solution and extracted with ethyl acetate (100 ml×3). The resulting organic phase was washed, in order, with a 10% citric acid aqueous solution and a saturated common salt solution, dried over anhydrous sodium sulfate and the solvent was removed by evaporation under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 5.14 g of methyl 1-(2-hydroxy-2-phenylethyl)indole-4-carboxylate as a yellow oily substance. The yield thereof was found to be 91%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.C(N)C.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:8]2[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[N:6]=[CH:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCCCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN
Solvent: CN(C)C=O
Product: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (15.85 mmol) of 4-(3-hydroxypropyl)-1H-imidazole and 5.5 ml (54.3 mmol) of dry ethylamine in 15.6 ml of dimethylformamide is treated with 4.86 g (17.4 mmol) of triphenylmethyl chloride in 5 ml of dimethylformamide under nitrogen. The mixture obtained is stirred at room temperature for 2 hours and is then poured onto 350 g of crushed ice. The resulting solid is collected by filtration, washed three times with water and purified on a chromatographic column using, as eluent, chloroform and then a chloroform/methanol (1/1) mixture to give 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole, M.p.: 132°-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[Br:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[C:8]([O:11][CH2:25][CH2:24][CH2:23][Br:22])=[CH:9][CH:10]=1)=[O:4]
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 6-hydroxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.20 g, 4.05 mmol) and 1,3-dibromopropane (4.09 g, 20.3 mmol) in acetone (125 mL) was added potassium carbonate (2.80 g, 20.3 mmol). The reaction mixture was heated to reflux for 3 hours and allowed to cool back down to room temperature. The mixture was partitioned between ethyl acetate and brine, and the layers were separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude oil was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 9/91) to give 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.23 g, 73%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 8.03 (d, 1H), 7.99 (s, 1H), 7.61 (AA′BB′, 4H), 7.02 (d, 1H), 4.18 (t, 2H), 3.88 (s, 3H), 3.43 (t, 2H), 2.23 (m, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15].C[O-].[Na+]>CO>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]([CH3:12])[C:19](=[O:20])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1C(=O)NC(=O)N(Cc2ccccc2)C1=O

Procedure:
To a suspension of 21.83 g (145 mmol) of benzylurea and 25 ml (145 mmol) of diethyl methylmalonate in 74 ml of methanol, 35.4 ml (145 mmol) of a 4.1M sodium methylate solution was added at room temperature, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. After the residue was dissolved in water and insoluble substances were filtered out, the filtrate was adjusted to pH 3-4 by adding concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and n-hexane-diethyl ether and dried to yield 30.11 g (84.8%, white crystal) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC.CN(C=O)C.[F-].[K+]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:18]([O:17][C:15]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)=[CH2:16])[CH3:19]
Reactant: CSc1nccc(Cl)n1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(OCC)c1ccnc(SC)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture comprising 16.4 g of 4-chloro-2-methylsulfanylpyrimidine, 38 g of tributyl(1-ethoxyvinyl) tin, 1.43 g of bis(triphenylphosphine)palladium (II) dichloride and 100 ml of DMF was stirred at 80° C. for 3 hours. After cooling the reaction mixture, 300 ml of ethyl acetate and 17.8 g of potassium fluoride were added to the mixture, and the resulting mixture was stirred at room temperature overnight. After filtration with Celite, the filtrate was washed, dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethylacetate=20:1) to give 18.9 g of 4-(1-ethoxy-vinyl)-2-methylsulfanylpyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCc2cccc3ccccc23)c1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), 1-(chloromethyl)naphthalene (5.40 ml), potassium carbonate (6.24 g), methyl iodide (a catalytic amount) and acetone (50 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was mixed with water (200 ml) and was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 2 hours. After being cooled to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-(1-naphthylmethoxy)benzoic acid (7.14 g) as colorless crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC=Cc1ccco1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: O=C(O)CCCCCCCCc1ccco1
Yield: 93.6 %

Procedure:
This compound was synthesized from 9-(2-furyl)-8-nonenoic acid (0.89 g, 4 mmol) by a hydrogenation reaction using Pd/BaSO4 (90 mg). Crystallization (petroleum ether) afforded the product (0.84 g, 93%) as white crystals (mp 31-32° C.); IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.30 (m, 8H), 1.63 (m, 4H), 2.35 (t, 2H), 2.60 (t, 2H), 5.95 (s, 1H), 6.27 (s, 1H), 7.28 (s, 1H), 9.85 (bs, 1H). Anal. Calcd. for C13H20O3 : C, 69.61, H, 8.99%; Found: C, 69.42, H, 9.04%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>C(N(CC)CC)C.C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C:27]([OH:31])([C:22]4[N:23]=[CH:24][CH:25]=[CH:26][N:21]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a pressure tube containing 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (550 mg, 1.44 mmol), copper(I) iodide (27.48 mg, 0.14 mmol), bis(triphenylphosphine)palladium(II) chloride (101.29 mg, 0.14 mmol) in triethylamine (4 mL) and THF (4 mL), was added 2-(pyrimidin-2-yl)but-3-yn-2-ol (427.62 mg, 2.89 mmol). The reaction was sealed and stirred at 55° C. for 1 hr. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (Biotage, 5-10% methanol in DCM followed by 10-20% [7M NH3 in methanol] in DCM) to give the title intermediate as an orange/brown oil: 1H NMR (250 MHz, DMSO) delta 1.92 (3H, s), 6.27 (1H, s), 6.98 (3H, s), 7.09 (1H, d, J=5.5 Hz), 7.26 (1H, d, J=9.5 Hz), 7.50 (1H, t, J=4.9 Hz), 8.20-8.41 (3H, m), 8.73-9.02 (2H, m); LC-MS: m/z=+402.00 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1.Br[C:23]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:24]=1[CH2:25][O:26][C:27](=[O:38])[N:28]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][CH3:30]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:6]=[C:7]([C:23]2[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][C:24]=2[CH2:25][O:26][C:27](=[O:38])[N:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH3:30])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1Br
Reactant: COC(=O)Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCN(Cc1ccccc1)C(=O)OCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 15, Step 3, using the following starting materials: [4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester and benzyl-ethyl-carbamic acid 2-bromo-5-trifluoromethyl-benzyl ester.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[NH:29][CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[OH:36][CH2:37][CH:38]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:34])=[C:21]([NH:23][C:24]([N:26]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH2:38][CH2:37][OH:36])[CH2:28][CH2:27]4)=[O:25])[CH:22]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCNC2(CC2)C1
Reactant: O=CCO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1NC(=O)N1CCN(CCO)C2(CC2)C1
Reaction time: 12 h

Procedure:
A solution of N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D8 (0.05 mmol), 2-hydroxyacetaldehyde (0.6 mmol) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords N-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenyl)-4-(2-hydroxyethyl)-4,7-diazaspiro[2.5]octane-7-carboxamide D10. 1H NMR (400 MHz, d6-DMSO) δ 9.67 (s, 1H), 8.79 (s, 2H), 7.95 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.60 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.26 (t, J=76.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.89 (m, 2H), 2.77 (m, 2H), 2.54 (m, 2H), 2.51 (m, 4H), 2.10 (s, 3H), 0.50-0.62 (m, 4H). MS (m/z) (M+1)+: 525.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[OH:23].[CH2:24](O)[CH2:25][CH2:26][CH3:27].C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:24]([O:23][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)c1c(O)c2cc(F)ccc2c(=O)n1CC(C)(C)C
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 6-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.21 g, 10 mmol), 1-butanol (1.4 ml, 15 mmol) and tributylphosphine (5.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added 1,1′-azodicarbonylpiperidine (5.05 g, 20 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.55 g, 94.2%) as an oil.