Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C@H:45]3[CH2:50][CH2:49][C@H:48]([CH:51]=O)[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)#[N:32]>C1COCC1>[F:2][CH2:3][CH2:4]/[CH:5]=[CH:51]/[C@H:48]1[CH2:49][CH2:50][C@H:45]([C@H:42]2[CH2:43][CH2:44][C@H:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH2:40][CH2:41]2)[CH2:46][CH2:47]1
Reactant: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](/C=C/CCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.0 g, 37.2 millimols) with THF (75 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.2 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(4-cyanophenyl)cyclohexyl)cyclohexanecarbaldehyde (10.0 g, 37.2 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 3, to obtain raw (E)-4-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)benzonitrile (9.9 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:21]=[C:20]([CH2:22]O)[CH:19]=[C:18]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH3:3].P(Br)(Br)[Br:28].Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:21]=[C:20]([CH2:22][Br:28])[CH:19]=[C:18]([CH2:24][CH2:25][CH3:26])[C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1Oc1ccccc1CC(=O)OC
Reactant: BrP(Br)Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1cc(CBr)cc(CCC)c1Oc1ccccc1CC(=O)OC

Procedure:
To a solution of 2.66.1 g (7.46 mmol) of the product of Step A dissolved in 15 mL of carbon tetrachloride was added 0.709 mL (7.47 mmol) of phosphorous tribromide and the reaction mixture was magnetically stirred at room temperature for 30 min as hydrogen bromide was evolved. The magnetic stir bar was removed, and the reaction mixture was concentrated in vacuo. The residue was redissolved and evaporated from carbon tetrachloride several times to remove most of the hydrogen bromide. Finally, the residue was purified by rapid flash chromatography on a silica gel column eluted with 10% EtOAc-hexane. Combination and evaporation of the purified fractions and drying in vacuo afforded 2.129 (68%) of the title compound which was used directly in the next step without further characterization.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[C:19]([O:21][CH:22]1[CH:29]2[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2)=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[CH:29]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]([CH2:24]3)[CH:22]1[O:21][C:19]([N:10]1[CH2:9][CH2:8][C:7]([CH2:13][C:14]([OH:16])=[O:15])([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:17])[CH2:12][CH2:11]1)=[O:20])[CH2:28]2
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: Cc1ccccc1C1(CC(=O)O)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccccc1C1(CC(=O)O)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
A fraction of the above aqueous solution (contains ˜15 mg of 2-(4-o-tolylpiperidin-4-yl)acetic acid, 0.064 mmol) was mixed with 2-adamantyl chloroformate (15 mg, 1.1 equiv). i-Pr2NEt (100 μL, excess) was added. Acetonitrile was added to make the mixture homogeneous. After stirring for 1 h at rt, the mixture was acidified and purified by prep HPLC to afford 2-(1-(2-adamantyloxycarbonyl)-4-o-tolylpiperidin-4-yl)acetic acid (4.4 mg). LC-MS Method 1 tR=2.13 min, m/z=412, 1H NMR (CDCl3) [selected resonances] 7.14 (m, 4H), 4.82 (s, 1H), 3.72 (br s, 2H), 2.78 (s, 2H), 2.52 (s, 3H), 2.46 (dt, 2H), 2.0 (m, 5H), 1.06 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](=[CH:23]\[CH3:24])/[C:20](Cl)=[O:21]>C1COCC1.C(OCC)(=O)C>[CH2:11]=[C:12]1[N:13]=[C:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:15][C:16](=[O:25])/[C:17]/1=[CH:18]/[C:19](/[C:20]([C:10]1[N:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[CH:3][C:2]=1[CH3:1])=[O:21])=[CH:23]\[CH3:24]
Reactant: Cc1cc2ccccn2c1
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
A solution of 2-methylindolizine (11.5 g; 87.7 mmol) in 35 mL of THF is added dropwise to a suspension of (2E)-2-[(E)-(4-methylidene-6-oxo-2-phenyl-4H-1,3-oxazin-5(6H)-ylidene)methyl]but-2-enoyl chloride (25 g; 87.7 mmol) in 140 mL of THF at 0° C. under nitrogen. After 18 h of stirring at ambient temperature, the reaction medium is diluted in ethyl acetate, and the solution is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM) to give 22.75 g (69%) of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[N+:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])#[C-:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:23]=[N:22][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:7]1[C:6]([CH3:13])([CH3:14])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: CC1(C)C(=O)Nc2ccc(F)cc2N1C(=O)N1CCCC1
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)c1ncn2c1C(C)(C)N(C(=O)N1CCCC1)c1cc(F)ccc1-2

Procedure:
Following the general procedure for EXAMPLE 30 and making non-critical variation but starting with 6-fluoro-1,2,3,4-tetrahydro-3,3-dimethyl-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 32, 0.750 g) and t-butyl isocyanoacetate (0.436 g) are converted to the title compound. After crystallization from ethyl ether/hexane, mp 168.5°-169.5°; MS (m/z) at 414; IR (mineral oil) 1713, 1668, 1520, 1181 and 1155 cm-1 ; NMR (CDCl3) 1.63, 1.8, 1.92, 2.08, 2.95, 3.23, 3.58, 6.52, 6.71 and 7.92 δ.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH3:31])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: CNCCCO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(C)CCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 3-(methylamino)propan-1-ol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 4.52 (br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.40 (t, 2H), 2.31 (t, 2H), 2.25 (t, 2H), 2.09 (s, 3H), 1.74 (m, 2H), 1.52 (m, 2H), 1.39 (m, 4H), 1.29 (m, 2H); MS (ESI): 523.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH3:12])[CH:3]=1>CCOCC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Solvent: CCOCC
Product: Cc1cc(Br)ccc1CO
Reaction time: 3 h

Procedure:
A solution of methyl 4-bromo-2-methyl-benzoate (1.05 g, 4.58 mmols) in 10 mL of Et2O was cooled to 0° C. and treated with LiAIH4 (177.0 mg, 4.58 mmols), stirred for 3 hours, and then carefully quenched with H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concentrated under reduced pressure. The title compound, 830.0 mg (90%), was isolated by column chromatography (10-30% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:32]=[CH:31][C:10]3[N:11]=[C:12]([CH2:14][C:15]4[O:19][C:18]([CH:20]5[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]5)=[N:17][N:16]=4)[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[CH2:23][CH:20]([C:18]2[O:19][C:15]([CH2:14][C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH:32]=[CH:31][C:10]=4[N:11]=3)=[N:16][N:17]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc3nc(Cc4nnc(C5CNC5)o4)sc3c2)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-(5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)azetidine-1-carboxylate (150 mg, 0.33 mmol) (prepared as described in compound 1c) in CH2Cl2 (2 mL) was added TFA (0.5 mL, 6.69 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure to give a Compound 42a as brownish oil (115 mg, 99% yield), which was used directly in the next step without further purification. LCMS ESI 349.1 (M+MeOH+H), RT=1.68 min (Method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)c(Cl)cc1Cl

Procedure:
This compound was prepared in a manner similar to Example 1 Step F using 2,4-dichloro-5-nitrotoluene (62.0 g, 0.3 mole), N-bromosuccinimide (160.2 g, 0.9 mole), benzoyl peroxide (2.0 g) and carbon tetrachloride (500 ml) to yield (2,4-dichloro-5-nitrophenyl)methyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].Cl[Si](C)(C)C.[CH3:21][CH2:22]O>>[CH2:10]([C:9]1[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:2]([O:1][CH2:21][CH3:22])=[O:3])=[CH:15][CH:14]=1)[CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of ibuprofen 1A (9.89g, 48 mmol) in anhydrous EtOH (35 mL) was added chlorotrimethylsilane (18.27 mL, 144 mmol) at room temperature, and the mixture was stirred at the same temperature for 2 h. After the removal of the excess EtOH and chlorotrimethylsilane under reduced pressure, the oily residue was treated with ice-cold saturated NaHCO3 (150 mL), and the resulting mixture was extracted with hexanes (450 mL). The hexanes solution was washed with brine (3×50 mL), and dried over anhydrous Na2SO2. Evaporation of the solvent afforded ethyl 2-(4′-isobutylphenyl)propionate 2A (11.24 g, in 100% yield) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2sccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3sccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of ethyl alcohol and 25 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14](Cl)[C:15]([NH:17][CH:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[N:31]([CH3:32])[N:30]=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:35][C:33]([C:21]1[N:20]2[C:36](=[O:37])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH2:25][S:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)=[O:34])([CH3:5])[CH3:4]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Reactant: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1nnnc1SCC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)CCl)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
Trimethylchlorosilane(0.32 ml) and triethylamine (0.14 ml) were added to a solution of 7-dichloroacetamido-3-(1-methyl-1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid(374 mg) in chloroform(10 ml) and the reaction mixture was stirred at 5 - 7°C. for 1.5 hours to give 7-chloroacetamido-3-(1-methyl-1H-tetrazole-5-yl) thiomethyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added to a mixture of phosphorus pentachloride(176 mg), quinoline(0.12 ml) and chloroform(15 ml) at -50°C. The reaction mixture was stirred at -50°C for 3 hours and diluted with tetrahyrofuran(20 ml), which was cooled to -78°C. To this solution was added a methanol solution of lithium methoxide prepared from lithium(140 mg) and methanol (15 ml) at -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.2 ml). The solution was poured into water and extracted with chloroform. The chloroform solution was washed with water, dried (Na2SO4) and evaporated to give a residue. The aqueous layer in the extraction of chloroform was again extracted with ethyl acetate. The extracts were washed with water, dried (Na2SO4) and the solvent was removed by distillation under reduced pressure to afford a residue. The residual fractions obtained above were combined and dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired product. This precipitation process was repeated three times to give 200 mg of pure 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-(1-methyl-1H- tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 3.38 and 3.56(2H, AB-quartet, J=19 Hz), 3.46(3H, singlet), 3.78(3H, singlet), 3.82(3H, singlet), 4.20 and 4.55(2H, AB-quartet, J=12 Hz), 4.47(2H, singlet), 5.07(1H, singlet).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[S:27][C:20]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCOCC1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCOCC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 78.2 %

Procedure:
Prepared from 4-(prop-2-ynyl)morpholine (24 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (39 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=5 Hz, 1H), 7.59 (s, 1H), 7.03 (m, 1H), 6.53 (m, 3H), 3.79 (m, 6H), 3.59 (s, 2H), 2.66 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:17])=[O:16])(C)(C)C.[ClH:20]>O1CCOCC1.C(Cl)(Cl)Cl>[ClH:20].[CH3:18][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7])(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccccc1CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.3 %

Procedure:
(2-Methanesulfonyl-benzyl)-carbamic acid tert-butyl ester (1.55 g, 5.43 mmol) was dissolved in warm dioxane (50 mL) and cooled to room temperature. HCl solution (4M solution in dioxane, 20 ml, 80 mmol) was added. After 20 h, a white precipitate had formed. The reaction was diluted with CHCl3 (50 mL) and filtered. The white solid was washed with CHCl3 and dried in-vacuo to yield 1.075g of 2-methanesulfonyl-benzylamine hydrochloride as an off white solid, m/z 186.6 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[CH2:17]([N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([OH:35])[CH:31]=2)[N:26]=[CH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][C:29]([O:36][CH3:37])=[C:30]([O:35][CH:14]3[CH2:15][CH2:16][C:11]4([O:10][CH2:9][CH2:8][O:7]4)[CH2:12][CH2:13]3)[CH:31]=2)[N:26]=[CH:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CCC2(CC1)OCCO2
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
At 50° C. 16.0 g potassium carbonate and 20.0 g of 8-methanesulphonyloxy-(1,4-dioxa-spiro[4,5]decan are added to 20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N,N-dimethylformamide and the mixture is vigorously stirred for 18 hours at 80° C. To complete the reaction potassium carbonate and 8-methanesulphonyloxy-(1,4-dioxa-spiro[4,5]decane are each added three times more and in each case the mixture is stirred for several hours at 80° C. The reaction mixture is cooled and slowly combined with a total of 500 ml of water. The precipitate is suction filtered, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](N(OC)C)=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=[O:19])[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (0.27 g, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (2.3 mL, 6.9 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (0.165 g, 71%). LCMS calculated for C17H15FNO(M+H)+: m/z=268.1. Found: 268.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH3:14][CH:15]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH3:16]>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH:15]([CH3:16])[CH3:14])([CH3:22])[CH3:21]
Reactant: CC(C)SC(C)(C)C=O
Reactant: CC(C)(S)CNc1ccccc1N
Product: CC(C)SC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 28.2 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.515 g, 2.65×10-3 mol) and 0.786 g (5.31×10-3 mol, 200 M %) 2-(1-methylethylthio)-2-methylpropanal were reacted by the method of Example 2 to give 2-(2-mercapto-2-methylpropylamino)-1-[2-(1-methylethylthio)-2-methylpropylamino]benzene 0.244 g (28% yield) as a colorless oil after purification by radial chromatography on a 2 mm silica gel plate eluting with 100 ml 100% petroleum ether and 200 ml 5% diethyl ether/petroleum ether.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(C(C)C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)c1nc(C=O)cs1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 3.1 g (15.6 mmol) of ethyl 2-isopropylthiazole-4-carboxylate in 50 ml of dichloromethane was cooled under N2 atmosphere to -78° C. and treated dropwise with 15.6 ml (23.4 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene over a period of 1.5 h. After being stirred for an additional 0.5 h, the solution was quenched with 5 ml of methanol followed by 15 ml of aqueous Rochelle's salt. The resulting mixture was partitioned between chloroform and aqueous Rochelle's salt, dried over Na2SO4, and concentrated to provide 1.37 g (56%) of the crude desired compound, Rf 0.47 (20% ethyl acetate in hexane). 1H NMR (CDCl3) δ 1.45 (d, J=7 Hz, 6 H), 3.39 (heptet, J=7 Hz, 1 H), 8.07 (s, 1 H), 10.00 (s, 1 H). Mass spectrum: (M+H)+ =156.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:44]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 10.99 g of isoamyl nitrite in 10 ml of acetonitrile was added to a mixture of 15.46 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(ethoxycarbonyl)methoxypyridine, 6.19 g of copper(I) chloride, 12.61 g of copper(II) chloride and 120 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 3 hours. This reaction solution was poured into a mixture of ice and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 13.16 g of 3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy)-2-(ethoxycarbonyl)methoxypyridine [present compound 7-8].