Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(B([C:10]#[C:11][CH2:12][CH2:13][CH2:14][Cl:15])OC(C)C)(CC)C.[CH3:16][OH:17]>>[Cl:15][CH2:14][CH2:13][CH2:12][C:11]#[C:10][C:16](=[O:17])[C@H:11]([CH3:10])[CH2:12][CH3:13]
Reactant: CO
Reactant: CCC(C)B(C#CCCCCl)OC(C)C
Product: CC[C@@H](C)C(=O)C#CCCCCl

Procedure:
[R]-(-)-9-chloro-3-methyl-5-nonyn-4-one was prepared by the method of Example 35 from sec-butyl(5-chloro-1-pentynyl)isopropoxyborane. [α]75D -12.84 (c 1.89, MeOH); IR (neat) 2213, 1671 cm1. 13C NMR (CDCl3) δ191.9, 92.2, 80.5, 50.0, 43.2, 30.5, 25.8, 16.4, 15.5, 11.4. MS m/e % (chemical ionization) 187 (100).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([OH:14])=O)([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([Cl:17])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1CCC(=O)Cl

Procedure:
A mixture of 3-(2-isopropylphenyl)propanoic acid (prepared in 3 steps from 1-isopropyl-2-iodobenzene, 2.01 g, 10.5 mmole), thionyl chloride (4.30 ml, 59.0 mmole) and toluene (40 ml) was refluxed for 2 hours. Concentration in vacuo gave 3-(2-isopropylphenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude. Step 2:
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=O.C(N1C2C(=CC=CC=2)C=C1C)CCCCCCC.C(N(CC)C1C=C(OCC)C=CC=1)C.C(OC(=O)C)(=O)C>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:6]1([C:7]2[C:2](=[N:1][CH:10]=[CH:9][CH:8]=2)[CH2:3][O:5]1)=[O:11]
Reactant: O=C1OC(=O)c2ncccc21
Agent: CCCCCCCCn1c(C)cc2ccccc21
Agent: CCOc1cccc(N(CC)CC)c1
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1OCc2ncccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 303.5 %

Procedure:
6.0 g of quinolinic anhydride, 9.5 g of N-octyl-2-methylindole and 0.56 g of zinc chloride are stirred in 30 ml of glacial acetic acid at 20° C. for 5 hours. 6.6 g of 3-diethylaminophenetole and 8 ml of acetic anhydride are then added, after which the mixture is stirred at 50° C. for 21/2 hours. The product is precipitated with 30 % aqueous ammonia, separated from the aqueous phase and recrystallised from isopropanol, affording 16.5 g of the isomer-free 4-azaphthalide compound of the formula ##STR16## of melting point 113°-118° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:27]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(Oc2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 404.17 g/mol.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)[CH3:3].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1.C(N=[N+]=[N-])(=O)C1C=CC=NC=1>C1(C)C=CC=CC=1>[CH3:3][N:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:20](=[O:21])[NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:7]2)[CH3:1]
Reactant: O=C=Nc1cccnc1
Reactant: CN(C)c1ccc2c(c1)CCN2
Agent: [N-]=[N+]=NC(=O)c1cccnc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc2c(c1)CCN2C(=O)Nc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
5-(N,N-dimethylamino)indoline (D13) (0.29 g, 1.79 mmol) was added to solution of 3-pyridylisocyanate derived from nicotinoyl azide (0.52 g, 1.2 eq) heated at reflux in dry toluene for 1.5 h. The solution was allowed to stand overnight evaporated under reduced pressure and purified by column chromatography (SiO2, CHCl3 /MeOH 2-5%) to afford a pale blue oil which on trituration with Et2O afforded a pale blue solid (550 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=S)[CH:9]2C)=[O:5])[CH3:2].C([OH:20])C>[Ni]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=[O:20])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1cc(C)c2c(c1)C(C)C(=S)N2
Agent: [Ni]
Product: CCOC(=O)c1cc(C)c2c(c1)CC(=O)N2
Yield: 67 %

Procedure:
An 0.80 g (3.01 mmol) portion of the 5-ethoxycarbonyl-7-methyl-3-methylthio-2-oxindole in 130 ml of absolute ethanol was treated with Raney Nickel by the above described procedure to give 0.44 g (2.01 mmol, 67% yield) of 5-ethoxycarbonyl-7-methyl-2-oxindole, m.p. 238°-241°;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:27])[CH3:26])[CH:20]=4)=[N:14][CH:15]=3)[N:10]([CH3:28])[C:9]2=[O:29])[CH:7]=1.[CH3:31][C:32]1[N:33]=[CH:34][N:35]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=2)[C:40](O)=[O:41])[CH:36]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:27][N:25]([CH3:26])[C:21]1[CH:20]=[C:19]([NH:18][C:13]2[N:12]=[C:11]3[N:10]([CH3:28])[C:9](=[O:29])[N:8]([C:6]4[CH:7]=[C:2]([NH:1][C:40](=[O:41])[C:39]5[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=[C:37]([N:35]6[CH:36]=[C:32]([CH3:31])[N:33]=[CH:34]6)[CH:38]=5)[CH:3]=[CH:4][C:5]=4[CH3:30])[CH2:17][C:16]3=[CH:15][N:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(N)cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(N4Cc5cnc(Nc6cccc(N(C)C)c6)nc5N(C)C4=O)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
To a solution of 3-(5-amino-2-methyl-phenyl)-7-(3-dimethylamino-phenylamino)-1-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (52 mg, 0.13 mmol), 3-(4-methyl-imidazol-1-yl)-5-trifluoromethylbenzoic acid (42 mg, 0.15 mmol), and DIEA (78 μL, 0.45 mmol) in DMF is added HATU (59 mg, 0.15 mmol), and the mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with EtOAc and washed with 5% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution, and brine. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The residue is purified by recrystallization from methanol to give N-{3-[7-(3-dimethylamino-phenylamino)-1-methyl-2-oxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl]-4-methyl-phenyl}-3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzamide (25 mg, 30%) as a yellowish solid; 1H NMR 400 MHz (DMSO-d6) δ 9.34 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.65 (d, 1H), 7.34-7.30 (m, 2H), 7.08-7.03 (m, 2H), 6.33 (d, 1H), 4.68 (d, 1H), 4.51 (d, 1H), 3.35 (s, 3H), 2.88 (s, 6H), 2.17 (s, 3H), 2.14 (s, 3H); MS m/z 656.3 (M+1).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11].C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[O:7]([C:10]([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N1CCNC1=O
Reactant: [O-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCN1C(=O)Oc1ccccc1

Procedure:
12.7 parts by weight of sodium phenolate were dissolved in 120 parts by volume of 80% strength tetrahydrofurane and the solution was adjusted to pH = 8. 14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were now introduced while stirring and keeping the pH value constant at 8 by simultaneous addition of triethylamine. The mixture was further stirred until the pH remained constant even without addition of triethylamine. 100 parts by volume of water were now added, the tetrahydrofurane was stripped off in vacuo, the residue was adjusted to pH = 10 with sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic solution was washed with water, dried over MgSO4 and evaporated and the residue was dried under an oil pump at 60°C for 1 hour and recrystallized from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6]NC2C3C(=CC=CC=3)N=C(C)C=2C(=O)C)=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([CH2:35][CH3:36])[C:26]=1[C:37]([O:39][CH3:40])=[O:38].BrC1C=CC(CBr)=CC=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([CH2:35][CH3:36])[C:26]=2[C:37]([O:39][CH3:40])=[O:38])=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: CCc1nc2ccccc2c(N)c1C(=O)OC
Agent: BrCc1ccc(Br)cc1
Product: CCc1nc2ccccc2c(NCc2ccc(Br)cc2)c1C(=O)OC

Procedure:
Methyl 4-(4-bromobenzylamino)-2-ethylquinoline-3-carboxylate was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 4-amino-2-ethylquinoline-3-carboxylate and 4-bromobenzyl bromide. MS(ES+): 399/401.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12](OCC)(OCC)OCC.Cl(O)(=O)(=O)=O>CCOCC>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:11])[CH:10]=[CH:12][O:1]2)=[CH:4][CH:5]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(OCC)OCC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: O=c1ccoc2cc(O)ccc12
Yield: 53.2 %

Procedure:
To a round bottomed flask, 0.26 mol of 2′,4′-dihydroxyacetophenone was added and mixed thoroughly with 232 mL of triethyl orthoformate. Then 26.4 mL of perchloric acid was dropped slowly into the resultant mixture. After 30 min reaction, 300 mL ether was added, and solids were precipitated. Following sucking filtration, the dried solids were transferred into a 1000 mL round bottomed flask, and refluxed for 2 hours after 250 mL hot water was added. Sucking filtration was conducted again, and then 22.69 g of 7-hydroxychromone was obtained by recrystallization with ethanol, with a yield of 53.2% and MS m/z (M)162.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=O)[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:24]([C:26]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=1)=[S:27])[NH2:25]>Cl.O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20](=[N:25][NH:24][C:26]([NH:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]([N+:39]([O-:41])=[O:40])[CH:30]=3)=[S:27])[CH3:21])[C:15]=2[OH:23])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
Dimethylformamide (1 ml) and conc. hydrochloric acid (1 drop) were added to 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (60 mg, 0.21 mmol) synthesized in Synthetic Example 1 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (57 mg, 0.21 mmol) synthesized in Reference Synthetic Example 56, and the mixture was stirred at room temperature for 21 hours. Water was added, and the precipitated solid was filtered, purified with a silica gel column chromatography (n-hexane/ethyl acetate=1/1 then chloroform/methanol=95/5). The obtained solid was extracted with ethyl acetate, washed with a saturated ammonium chloride aqueous solution, saturated sodium chloride aqueous solution. The organic layer was concentrated to obtain the desired product as a pale yellow solid (104 mg, yield 92%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH:47]=[O:48])([CH3:46])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)([CH3:46])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CC1(C=O)CCCN(C(=O)OC(C)(C)C)C1
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC

Procedure:
3-{Hydroxy-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methyl}-3-methyl-piperidine-1-carboxylic acid tert-butyl ester was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 3-formyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2002024679) following general procedures as described in these Examples.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:26]([O:28]CC)=[O:27])=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:26]([OH:28])=[O:27])=[C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2Cc1ccccc1
Yield: 100 %

Procedure:
Saponification of ethyl 1-benzyl-6-(benzyloxy)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (2.04 g, 5.04 mmol) as described for intermediate 2 gave 1.90 g (100% yield) of the title acid as white crystals; mp 191° C. (dec), (ethyl acetate). 1HNMR 400 MHz (DMSO-d,) δ (ppm): 3.58 (2H, t, J=8.8 Hz, CH2), 4.05 (2H, t, J=8.8 Hz, CH2), 4.53 (2H, s, NCH2), 4.93 (2H, s, OCH2), 7.32-7.45 (10H, m, aromatics), 13.41 (1H, s, OH). Anal. Calcd for C21H19N3O4: C 66.83; H, 5.07; N, 11.13. Found: C, 66.73; H, 5.16; N, 10.97.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.O>O1CCCC1>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:22])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
In a 300 mL three-neck flask were put 10 g (92 mmol) of 2-aminophenol and 7.0 mL of triethylamine and was added 100 mL of tetrahydrofuran (THF). The solution was stirred at 0° C. for 20 minutes. After the stirring, a solution in which 0.10 mol of 4-iodobenzoyl chloride was dissolved in 100 mL of tetrahydrofuran (THF) was dropped. The solution was stirred at 0° C. for 5 hours under a nitrogen stream. After the stirring, the solution was added to about 300 mL of water and an aqueous layer of the obtained mixture was extracted with ethyl acetate. After the extraction, the extracted solution was combined with the organic layer and washed with 1 M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and brine in this order. After the washing, magnesium sulfate was added into the organic layer to dry the organic layer. After the drying, the mixture was subjected to suction filtration through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855) to give a filtrate. The solid, which was obtained by condensation of the obtained filtrate, was recrystallized with a mixed solvent of ethyl acetate and hexane to give 30 g of a powdery white solid in a yield of 97%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[N:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C([Sn]([N:43]=[N+:44]=[N-:45])(CCCC)CCCC)CCC>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[NH:45][N:44]=[N:43][N:24]=2)=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)C1=C(COCC#N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(COCc2nnn[nH]2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 81.2 %

Procedure:
A solution of [4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxyacetonitrile (3.52 g) and tri-n-butyltin azide (3.00 g) in dioxane (100 ml) was heated under reflux for 21.5 hours and then evaporated. The residual oil was taken up in diethyl ether (200 ml) and dry halogen chloride was bubbled through the stirred solution in a slow stream for 50 minutes. The resulting precipitate was collected, washed with diethyl ether and dried to give the title compound (3.14 g), m.p. 112°-114° C.
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8].O>CCOCC.[NH4+].[Cl-]>[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Lithium borohydride (22 0mg) was added in a single portion to a stirred solution of methyl 3-bromo-5-(trifluoromethyl)benzoate (2.46 g) in ether (60 ml) containing water (156 ml). The resulting solution was stirred for 4 hours at room temperature, at which point the reaction mixture was diluted with saturated aqueous NH4Cl solution (50 ml). The organic layers were separated, dried over MgSO4, filtered and the solvent removed under reduced pressure to give 3-bromo-5-(trifluoromethyl)benzyl alcohol as a clear oil (2.1 g).1H NMR (360 MHz,CDCl3) δ 1.83 (1H, br s), 4.76 (2H,s), 7.47 (1H, s), 7.56 (1H, s), 7. 68 (1H, s).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][OH:9].[Mn]([O-])(=O)(=O)=[O:19].[K+].S([O-])(O)=O.[Na+].Cl>O>[CH3:6][CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:19])=[O:9]
Reactant: CCCCCCCCC(C)CO
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: O
Product: CCCCCCCCC(C)C(=O)O
Temperature: 0 °C
Yield: 268.4 %

Procedure:
After 14.6 g of concentrated sulfuric acid and 8.6 g (50 mmol) of (-)-2-methyldecanol were added to 96 ml of water, 16.4 g (10.4 mmol) of potassium permanganate was added dropwise over 4 hours while the reaction temperature was held below 25° C. The thus obtained reaction mixture was poured into 300 ml of ice water, added with 30 g of sodium hydrogen sulfite, adjusted to pH of not more than 1 with hydrochloric acid, extracted with ether and then extracted with a 10% aqueous solution of sodium hydroxide. This extract was added with hydrochloric acid to adjust pH to not more than 1 and again extracted with chloroform. The thus obtained extract was washed with water, dried, concentrated, and distilled under a reduced pressure (0.4 mmHg, 116°~120° C.) to obtain 5.2 g (yield 63%) of (+)-2-metyl decanoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20]>>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]([CH3:14])[C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1ncc(-c2ccc(O)cc2)cc1=O
Reactant: ClCCCBr
Product: Cn1ncc(-c2ccc(OCCCCl)cc2)cc1=O

Procedure:
5-[4-(3-Chloro-propoxy)-phenyl]-2-methyl-2H-pyridazin-3-one was prepared from 5-(4-hydroxy-phenyl)-2-methyl-2H-pyridazin-3-one with 1-bromo-3-chloro-propane using the procedure described in Example 86 Step 3; Mp 90-91° C.; MS m/z 279 (M+H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[C:5]([C:27]([F:30])([F:29])[F:28])[N:4]=1.C1COCC1>CO.[Pd]>[F:31][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([OH:19])=[O:18])=[C:5]([C:27]([F:30])([F:28])[F:29])[N:4]=1
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCc2ccccc2)c1NC(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)O)c1NC(C)C
Yield: 101.1 %

Procedure:
A mixture of 46.27 g (0.1 mol) of 3-methyl 5-benzyl 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (example 181 of U.S. Pat. No. 4,698,093) in 1.2 L of a 1:5 mixture of THF in methanol was hydrogenated using catalytic 5% Pd/C under 50 lb of hydrogen pressure for 48 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give 36 g of 3-methyl 5-hydrogen 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate. To a mixture of 34.7 g of this monoacid in 400 ml of carbon tetrachloride was added 23 g (0.11 mol) of phosphorus pentachloride. The reaction mixture was stirred at room temperature until HCl evolution stopped. The reaction mixture was held at reflux for 20 min and concentrated in vacuo affording 38.04 g of monoacid chloride as a yellow oil. A portion (3.75 g 0.01 mol) of this oil and 1.7 g (0.01 mol) of triethyl phosphite was heated to 160° C. and then cooled. The resulting oil was purified by HPLC (25% EtOAc in hexane) affording 2.09 g of (44%) of product as a thick yellow oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].O.[O:40]1CCOCC1>>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([OH:40])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(O)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
A solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-methoxy-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine (18 mg, 0.044 mmol) from Example 84, step 1, in water/dioxane was heated to 105° C. for 16 hr. Solvent was evaporated and the product purified by super critical chromatography (SFC) to give 4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-2-ol. MS (ES+): 390.