Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([NH2:14])(=[O:13])=[O:12])[C:2]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C[Al](C)C.C[O:20][C:21](=O)[NH:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1.O>C(Cl)Cl.Cl.C(O)(=O)C>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([O:31][CH3:32])[N:24]=[C:23]([NH:22][C:21]([NH:10][S:7]([C:2]2[C:1]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:9])=[O:8])=[O:20])[N:28]=1
Reactant: NS(=O)(=O)c1ccccc1S(N)(=O)=O
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(N)(=O)=O)n1
Temperature: 25 °C
Yield: 17 %

Procedure:
To a suspension of 0.7 g of 1,2-benzenedisulfonamide and 1.5 ml of trimethylaluminum in 70 ml of anhydrous methylene chloride was added 0.6 g of 4,6-dimethoxypyrimidin-2-ylcarbamic acid methyl ester under N2 with stirring. After addition, the mixture was stirred at room temperature for 30 minutes and was then heated to reflux for 12 hours. The reaction mixture was then cooled down to room temperature. To this mixture was added 50 ml of methylene chloride, 100 ml of water, 10 ml of acetic acid and 5 drops of concentrated hydrochloric acid. The mixture was then stirred at room temperature for 20 minutes and was filtered. The organic layer was then separated, washed with water, dried over sodium sulfate and concentrated. The residue was then chromatographed on silica gel (CH2Cl2 /acetic acid 1:1) to yield 0.2 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-1,2-benzenedisulfonamide, m.p. 192°-193° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (trans-4-hydroxycyclohexyl)carbamate (from AstaTech, 0.133 g, 0.618 mmol) and triethylamine (0.12 mL, 0.86 mmol) in methylene chloride (1 mL) was added methanesulfonyl chloride (0.057 mL, 0.74 mmol). The reaction mixture was stirred at room temperature for 2 h. After dilution with sat. aq. NaHCO3 solution, the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (0.18 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].COC1C=CC(C=CC(O)=O)=CC=1.S(Cl)(Cl)=O.Cl.[CH3:34][NH:35][CH3:36]>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([N:35]([CH3:36])[CH3:34])=[O:8]
Reactant: CNC
Reactant: COc1ccc2c(Cl)c(C(=O)O)sc2c1
Agent: COc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(Cl)c(C(=O)N(C)C)sc2c1

Procedure:
3.0 g of 3-chloro-6-methoxy-benzo(b)thiophene-2-carboxylic acid (7.0 g) synthesized from 4-methoxycinnamic acid (10.0 g) and thionyl chloride (15 ml) according to the method described in J. Med. Chem. 1992, 35, 958-965 was reacted with dimethylamine hydrochloride and triethylamine in THF to give the title compound (1.9 g) as a brown oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)C=CC=CC=1.Cl>C1COCC1.C(OCC)(=O)C.O>[Br:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:18]
Reactant: O=C1CCc2sccc21
Reactant: O=C(Oc1ccccc1)c1cccc(Br)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cccc(Br)c1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 58 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (2.1 g, 15.0 mmol) in 15 mL of THF was treated with NaH (60 percent, 1.5 g, 36 mmol). After the addition of 3-Bromo-benzoic acid phenyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(3-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol) as brown solid in 58% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC.Cl.[Cl-].[Na+]>C1COCC1.CCCCCCC>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:13]([OH:18])[OH:14])=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: OB(O)c1ccc(OC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
A solution of 1-bromo-4-(trifluoromethoxy)benzene (1.69 kg) and triisopropyl borate (1.46 kg) in THF (6.75 L) at −70° C. was treated with 2.25 M butyllithium in hexanes (3.27 L) over 2.3 hours, stirred for 10 minutes, treated with 6M HCl (1.52 L) over 50 minutes, stirred for 18 hours at room temperature, and poured into a mixture of heptane (8.43 L) and 20% (w/w) sodium chloride (8.44 kg). This mixture was stirred for 10 minutes and separated into an aqueous fraction and an organic fraction. The organic fraction was concentrated to provide a white paste. The paste was dried under vacuum (100 mmHg) at ambient temperature with a nitrogen bleed for 2 days then at 40-50° C. for 18 hours to provide 1.306 kg (90.4%) of the desired product as a solid. 1H NMR (CDCl3, 300 MHz) δ7.24-7.19 (m, 2H), 8.14-8.10 (m, 2H) with additional absorptions at 7.19-7.15 (m, 2H) and 8.04-8.00 (m, 2H) corresponding to the cyclic boronic acid trimer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[NH:16][N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.ClC1C=CC(C2N=C(N3CC(NCC)(C(N)=O)C3)N3C(=O)N(CC4C=CC(C(F)(F)F)=CC=4)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]3[C:15](=[O:18])[N:16]([CH2:32][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=4)[N:17]=[C:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(Cc4ccc(C(F)(F)F)cc4)c(=O)n23)C1
Product: Cc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)cc3)c(=O)n12

Procedure:
The title compound was prepared by coupling 7,8-bis(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one with 4-trifluoromethylbenzyl bromide in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-3-oxo-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=4.485 min, [M+H]30 =529.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:23]1[CH2:32][O:31][CH:30]2[CH:25]([CH2:26][CH2:27][NH:28][CH2:29]2)[O:24]1>C1C=CC=CC=1>[CH2:23]1[CH2:32][O:31][CH:30]2[CH:25]([CH2:26][CH2:27][N:28]([C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:29]2)[O:24]1
Reactant: C1CC2OCCOC2CN1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC2OCCOC2C1
Reaction time: 8 h

Procedure:
To a stirred solution of 24 parts of diphenylacetyl chloride in 250 parts by volume of benzene is added 15 parts of solid sodium carbonate and 16.4 parts of 4-(ethylenedioxy)piperidine. The resultant mixture is refluxed for about 29 hours, left overnight at room temperature, and filtered. The filtrate is washed twice with 10% hydrochloric acid, twice with saturated sodium bicarbonate solution and once with brine. The filtrate is then dried over magnesium sulfate, concentrated and recrystallized from cyclohexane to afford 4-(ethylenedioxy)-1-(diphenylacetyl)piperidine, melting at about 136°-137° C. This compound has the following structural formula ##STR20##
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(C(C)C)CC)(C)C.[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:45])[CH2:41][O:42][CH2:43][CH3:44])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([C@H]1COC(=O)N1)C1C=CC=CC=1.[CH:59]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[CH:68]=2)=[CH:63][CH:62]=1)=[O:60].OO>ClCCl.O.CO>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:45])[C@@H:41]([O:42][CH2:43][CH3:44])[C@@H:59]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[C:69]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:79])([CH3:78])[CH3:80])[CH:68]=2)=[CH:63][CH:62]=1)[OH:60])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(C=O)cc2)c1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(-c2cccc(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
72.3 ml (72.3 mmol) of dibutylboron triflate and then 12.6 ml (72.3 mmol) of diisopropylethylamine are added dropwise to a solution, cooled to 0° C., of 15.2 g (57.8 mmol) of (S)-4-benzyl-3-(2-ethoxyacetyl)oxazolidin-2-one, prepared as described in the publication by Bernard Hulin et al., J. Med. Chem., 1996, 39, 3897-3907, from commercial (S)-4-benzyloxazolidin-2-one, in 150 ml of dichloromethane. The reaction medium is stirred at 0° C. for 30 min and then cooled to −78° C. A solution of 15 g (48.2 mmol) of tert-butyl (4′-formylbiphenyl-3-yl)methylcarbamate in 70 ml of dichloromethane is then added dropwise. After stirring from −78° C. to ambient temperature over 4 hours, the reaction medium is cooled to 0° C. and a mixture of 130 ml of a buffer solution, pH=7, and of 100 ml of methanol is added dropwise, followed by the dropwise addition of a mixture of 130 ml of aqueous hydrogen peroxide solution and of 100 ml of methanol. The reaction medium is stirred at 0° C. for 1 hour and then at ambient temperature for 3 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated under vacuum. The residue obtained is purified by chromatography on a silica column eluted with a mixture of heptane and ethyl acetate (70/30) and then increase in the polarity up to a 50/50 heptane/ethyl acetate mixture. After evaporation of the solvents, 28 g of tert-butyl {4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxopropyl]biphenyl-3-yl}methylcarbamate are collected. Yield=81%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[N:11]3[N:16]=[CH:17][C:18](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1)#[CH:21]>>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:20]#[C:21][C:18]2[CH:17]=[N:16][N:11]3[C:12]([CH2:14][OH:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: OCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: Nc1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)cn1

Procedure:
The title compound was prepared from [5-(4-chloro-phenyl)-3-iodo-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (example C.14 step 2) (193 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (111 mg, 59%). MS (ISP) 376.4 [(M+H)+]; mp 215-217° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[N:12]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:43]([O:47][C:48]([NH:50][NH2:51])=[O:49])([CH3:46])([CH3:45])[CH3:44]>>[C:43]([O:47][C:48]([NH:50][NH:51][C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[N:11]=[C:10]2/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: COc1c(C(=O)O)ccc2c1c(/C=C/c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Product: COc1c(C(=O)NNC(=O)OC(C)(C)C)ccc2c1c(/C=C/c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 112 %

Procedure:
94 mg of 3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid and 34.4 mg of hydrazine carboxylic acid tert-butyl ester were condensed in the manner as described in Example 127, to afford 126.9 mg of the title compound as pale yellow crude crystals.
Reaction SMILES: C(O)(=[O:3])C.[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.[Zn]>[C:5]([NH2:12])(=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Product: NC(=O)c1ccccc1
Yield: 24 %

Procedure:
Watanabe, in Bull. Chem. Soc. Japan, 37, 1325 (1964), teaches the conversion of benzonitrile to benzamide with precipitated copper and Urushibara copper (U-Cu). The precipitated copper was prepared from a cupric chloride solution and zinc dust and was reacted with benzonitrile in water for 8 hours to give a 7% yield of benzamide. U-Cu-A was prepared by mixing zinc dust with a solution of cupric chloride and then leaching the resultant product with 13% acetic acid. The reaction of benzonitrile in water with U-Cu-A for 8 hours gave a 24% yield of benzamide with no recovery of benzonitrile.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]>C(OCC)(=O)C>[F:35][C:36]1[C:41]([O:17][C:16](=[O:18])[C@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:5]([O:4][C:2]([CH3:19])([CH3:1])[CH3:3])=[O:6])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 99.7 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)phenylalanine (6.36 g, 24 mmol) in ethyl acetate (50 mL) at 0° C. was added to dicyclohexylcarbodiimide (4.95 g, 24 mmol) and pentafluorophenol (4.42 g, 24 mmol) in ethyl acetate (50 mL) at 0° C. The mixture was stirred for 2.75 h at 0° C. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate. The residue was dissolved in ethyl acetate. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate to give N-(1,1-dimethylethoxycarbonyl)phenylalanine pentafluorophenyl ester (10.32 g, quantitative).
Reaction SMILES: CO.[OH-].[Na+].[CH:5]([CH:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][S:9]1)([CH3:7])[CH3:6].C(OCC)C>O1CCCC1>[CH:5]([CH:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][S:9]1)([CH3:7])[CH3:6]
Reactant: COC(=O)CN1C=CSC(C(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)C1SC=CN(CC(=O)O)C1=O
Reaction time: 0.25 h

Procedure:
Methanol (0.15 ml) and a 1 N aqueous sodium hydroxide solution (0.34 ml) are added to a solution of methyl 2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate (70 mg, Reference compound No. 43-1) in tetrahydrofuran (0.15 ml) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred for 15 minutes. Diethyl ether is added to the reaction mixture, and the whole is extracted with water. 2 N Hydrochloric acid is added to the extract to acidify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference Compound (65.7 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(C)c(CSc2ccccc2)c(-c2ccc(F)c(C)c2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cc(C)c(CS(=O)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (tech. grade, approximately 75% peroxide; 1.19 g, aproximately 5 mmoles) was added in small portions to a stirred solution of (4'-fluoro-3,3',5-trimethyl-[1,1'-biphenyl]-2-yl-methyl) phenyl sulfide (1.68 g, 5 mmoles) at -78° C. The reaction mixture was then stirred at -78° C. for 30 minutes and allowed to warm to room temperature. The solution of the product was separated by filtration from the 3-chlorobenzoic acid which was washed with methylene chloride. The combined methylene chloride solutions of the product were diluted with methylene chloride to 100 ml then washed with dilute sodium hydroxide solution (2×50 ml) dried (MgSO4), filtered, and the solvent was evaporated in vacuo to leave 1.7 g of crude product. This was purified by flash chromatography on silica gel using a 40×150 mm column eluting with 3.5% (v:v) acetone in methylene chloride to give 1.55 g of the title compound as a gum. Dry toluene was added and evaporated in vacuo four times to dry the product, which then crystallized, m.p. 75°-85° C. Calc'd for C22H21FSO: C, 74.97; H, 6.01 Found: C, 75.01, H, 6.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=O)[CH:30]=2)[N:4]=1.[CH3:38][N:39]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.CN>CN(C=O)C>[CH3:38][NH:39][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37]
Reactant: CN1CCOCC1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Agent: CN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
70 mg of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, dissolved in DMF (5 ml) was treated at RT with 30 mg of 4-methylmorpholine, then cooled to 0° C. and further treated with 26 mg of 2-chloro-4,6-dimethoxy-1,3,5-triazine followed. The solution was stirred at RT for 90 minutes, then treated with 10 mg of metylamine hydrochloride and stirred for 12 h at RT. The mixture was partitioned between cold diluted HCl and EtOAc. The layers were separated, the organic layer washed with water, dried over Na2SO4 and the solvent was removed in vacuo. The solid residue was triturated with ether, filtered off and dried in a high vacuum to give 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl amide as a white crystalline solid. ISN mass spectrum, m/e 535.2 (M−1 calculated for C25H24N6O6S: 535).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][Si](C)(C)C)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.C([O-])([O-])=O.[K+].[K+]>CO>[C:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
A 250-mL round-bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet was charged with a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilyl)ethynyl)-1H-indazole (12.6 g, 42.2 mmol) in MeOH. To this solution, solid K2CO3 (0.58 g, 4.2 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 4 h. Upon completion by TLC, the reaction mixture was filtered, concentrated, and purified by silica gel chromatography (0-10% ethyl acetate in hexanes) to give the title compound (4.7 g) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.96 (s, 1H), 7.75 (d, 1H), 7.47 (dd, 1H), 5.86 (dd, 1H), 4.10 (s, 1H), 3.90-3.86 (m, 1H), 3.78-3.68 (m, 1H), 2.43-2.32 (m, 1H), 2.06-1.93 (m, 2H), 1.81-1.66 (m, 1H), 1.60-1.50 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=O)[C:15]3[CH:14]=[C:13]4[NH:18][C:19]([C:21]5[C:22](=[O:41])[NH:23][CH:24]=[CH:25][C:26]=5[NH:27][C@@H:28]([CH3:40])[CH2:29][C:30]5[C:35]([F:36])=[C:34]([F:37])[CH:33]=[C:32]([F:38])[C:31]=5[F:39])=[N:20][C:12]4=[CH:11][C:10]=3[C:9]2=[O:42])[CH2:4][CH2:3]1>C(O)(=O)C.[Zn]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:16][C:15]3[CH:14]=[C:13]4[N:18]=[C:19]([C:21]5[C:22](=[O:41])[NH:23][CH:24]=[CH:25][C:26]=5[NH:27][C@@H:28]([CH3:40])[CH2:29][C:30]5[C:31]([F:39])=[C:32]([F:38])[CH:33]=[C:34]([F:37])[C:35]=5[F:36])[NH:20][C:12]4=[CH:11][C:10]=3[C:9]2=[O:42])[CH2:4][CH2:3]1
Reactant: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3
Yield: 13.8 %

Procedure:
To a solution of (S)-6-(1-methylpiperidin-4-yl)-2-(2-oxo-4-(1-(2,3,5,6-tetrafluorophenyl)propan-2-ylamino)-1,2-dihydropyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (Compound 27) (0.30 g, 0.51 mmol) in 50 mL of acetic acid was added zinc powder (0.64 g, 7.65 mmol). The mixture was heated to reflux for 16 h and filtered through Celite. Acetic acid was removed under vacuum and the residue was taken up with 10 mL of MeOH. Reverse phase chromatography purification yielded the title compound as a white solid (40 mg, 13.7%). 1H NMR δ (500 MHz, DMSO-d6) 13.03 (d, J=3.0 Hz, 1H), 11.25 (br s, 1H), 11.11 (dd, J=5, 13 Hz, 1H), 7.96 (s, 0.5H, conformational isomer), 7.81 (s, 0.5H), 7.77 (s, 0.5H), 7.80-7.65 (m, 1H), 7.61 (s, 0.5H), 7.41-7.31 (m, 1H), 6.16 (d, J=12.0 Hz, 1H), 4.48 (s, 2H), 4.29-4.14 (m, 1H), 4.12-3.96 (m, 1H), 3.20-3.02 (m, 2H), 2.90 (d, J=18 Hz, 2H), 2.23 (s, 3H), 2.07 (t, J=18 Hz, 2H), 1.94-1.75 (m, 2H), 1.78-1.64 (m, 2H), 1.42-1.29 (m, 3H). ESI MS: m/z 569.2 (M+1).