Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][CH2:3][S:4][CH2:5][CH2:6][NH2:7].[C:8]1([S:18](Cl)(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(#[N:24])C>>[C:8]1([S:18]([NH:24][CH:3]([S:4][CH2:5][CH2:6][NH2:7])[CH3:2])(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CC#N
Reactant: NCCSCCN
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: CC(NS(=O)(=O)c1cccc2ccccc12)SCCN
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under ice cooling, 5.29 g of aminoethylthioethylamine was added dropwise with 120 mL of acetonitrile solution in which 1.00 g of 1-naphthalenesulfonyl chloride was dissolved, and the mixture was stirred at room temperature for two days. The reaction mixture was evaporated under reduced pressure, and then the residue was added with 500 mL of water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 1.50 g of 1-naphthalenesulfonylaminoethylthioethylamine.
Reaction SMILES: [CH:1]1[C:13]2CC3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].IC>CS(C)=O>[CH3:14][C:15]1([CH3:18])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:16]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CC1(C)c2ccccc2-c2ccccc21
Temperature: 10 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
A 2000 mL round flask was charged with 9H-fluorene (50 g, 300.1 mmol) and potassium t-butoxide (77.0 g, 721.9 mmol), and then 700 mL of DMSO was slowly injected thereto. Under nitrogen atmosphere, iodomethane (113.5 g, 800 mmol) was slowly dropped through a dropping funnel while the reactor temperature was maintained at 10° C. or lower. The mixture was stirred at room temperature for 24 hours, and the reaction was terminated by addition of 500 mL of distilled water. The organic layer collected by extraction with n-hexane was dried over magnesium sulfate, followed by removal of volatile materials, and then purified with n-hexane by using silica gel column chromatography tube, followed by drying, to thereby obtain 47.5 g of 9,9-dimethyl-9H-fluorene (yield: 81.50%) as white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:20]([C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(Oc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Oc3ccccc3)n2)sc2ccccc12
Yield: 27.1 %

Procedure:
A mixture of methyl thiosalicylate (0.34 g, 2.0 mmol), 2-cyano-6-phenoxypyridine (0.40 g, 2.0 mmol), triethylamine (0.45 ml, 3.1 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (0.18 g, 26%) as crystals.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:41][C:40]([CH3:43])([CH3:42])[C:39]([N:2]([CH3:1])[C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:44]
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (38.9 mg, 0.095 mmol) from Example 166 in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (24.77 μL, 0.142 mmol) followed by pivaloyl chloride (12.79 μL, 0.104 mmol), and the resultant reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-4). The title compound was eluted with a gradient of 0% to 100% ethyl acetate/hexanes over 15 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.81 (d, J=7.4, 1H), 7.74 (s, 1H), 7.60-7.55 (m, 2H), 7.43 (dd, J=6.6, 14.3, 1H), 5.45 (dd, J=7.0, 8.7, 1H), 4.35-4.29 (m, 1H), 3.57 (d, J=13.5, 1H), 3.44 (d, J=13.5, 1H), 3.13 (s, 3H), 2.73 (dd, J=2.6, 8.9, 1H), 2.53-2.45 (m, 1H), 2.41 (ddd, J=2.7, 8.3, 12.0, 1H), 2.37-2.32 (m, 1H), 2.29 (dd, J=3.0, 9.0, 1H), 2.26-2.21 (m, 1H), 2.05 (dq, J=6.0, 12.0, 1H), 1.86-1.80 (m, 3H), 1.55 (ddd, J=6.9, 12.8, 19.6, 2H), 1.41-1.31 (m, 1H), 1.30 (s, 9H), 0.88 (d, J=6.7, 3H), 0.82 (d, J=6.6, 3H); MS (ESI+) m/z 496 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[CH:16]=[C:17]([C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]C)=O)[CH:24]=2)[CH:18]=[C:19]([Br:22])[C:20]=1[OH:21].O>CCCCCC.C(Cl)(Cl)Cl>[CH2:7]([N:6]([CH3:5])[C:28]([C:25]1[CH:24]=[C:23]([C:17]2[CH:18]=[C:19]([Br:22])[C:20]([OH:21])=[C:15]([Br:14])[CH:16]=2)[O:27][N:26]=1)=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1cc(-c2cc(Br)c(O)c(Br)c2)on1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: CN(Cc1ccccc1)C(=O)c1cc(-c2cc(Br)c(O)c(Br)c2)on1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
Trimethylaluminium (0.1 mL of a 2 N solution in hexane, 0.2 mmol) was added to a solution of N-methylbenzylamine (27 mg, 0.22 mmol) in dry chloroform (2 mL) under nitrogen and the resulting solution was stirred at room temperature for 20 minutes. Methyl 5-(3,5-dibromo-4-hydroxyphenyl)isoxazole-3-carboxylate (75 mg, 0.2 mmol) was added and the reaction mixture was stirred at 50° C. for 48 hours. Water (1 mL) and chloroform (2 mL) were added to the solution; the chloroform was separated and evaporated to dryness. The residue was dissolved in dimethylsulphoxide (1 mL) and purified by preparative HPLC to give the title compound (42.8 mg, 46%) as a colorless powder. 1H NMR δ (ppm) (DMSO-d6): 2.96 and 3.09 (3 H, two s), 4.76 (2 H, s), 7.28-7.46 (6 H, m), 8.14 and 8.16 (2 H, t, two s), 10.73 (1 H, s). LCMS (10 cm_apci_formic) Rt 3.79 min; m/z 463/465/467 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:21].[K+].[K+].[OH2:28]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:28])=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: Clc1ccc(-c2[nH]ccc2Sc2ccccc2)cc1
Reactant: O
Agent: [K+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2-(p-chlorophenyl)-3-(phenylthio)pyrrole (1.0 g, 3.5 mmol) in methanol is treated with a solution of potassium peroxymonosulfate (2.95 g) in water (7.6 mL), stirred at room temperature for 5 hours, diluted with additional methanol, treated with a solution of potassium peroxymonosulfate (2.5 g) in water (7.4 mL), stirred at room temperature overnight and filtered to obtain a solid which is washed with water and dried to give the title product as a solid (mp 158°-159° C.).
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[CH:15]([N:18](CC)C(C)C)(C)C.C1(=O)N([O:29][C:30](=O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])C(=O)CC1>CN(C)C=O>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([C:5]1[CH:4]=[CH:13][CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=1[O:14][CH2:15][NH2:18])=[O:29])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1ccc(CN)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)CCCCCNC(=O)OC(C)(C)C)c1OCN
Reaction time: 18 h
Yield: 80 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (2.25 g, 10.3 mmoles) was suspended in anhydrous N,N-dimethylformamide (30 mL), and N,N-diisopropylethylamine (3.6 mL, 20.7 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (3.38 g, 10.3 mmoles). The mixture was stirred under dry nitrogen for 18 hours, during which time all solids dissolved. The solvent was then evaporated to leave a light brown syrup, which was partitioned between ethyl acetate (100 mL) and 1M aqueous hydrochloric acid (100 mL). The layers were separated, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate (100 mL) and saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to an amorphous off-white solid. The solid was crystallized form ethyl acetate/hexanes, filtered, and dried in vacuo to afford 3.25 g (80% yield) of methyl (N-tert-butoxycarbonyl-6-aminohexanoyl)-aminomethylsalicylate (m.p. 120°-121° C., open capillary, uncorrected).
Reaction SMILES: ON[C:3]([C@H:5]1[C:10]([CH3:12])([CH3:11])[S:9](=O)(=O)[CH2:8][CH2:7][N:6]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:4].[OH:31][CH2:32]C1C=CC(B(O)O)=CC=1.B(O)[OH:43].O=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:32][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]([S:15]([N:6]3[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[C@@H:5]3[C:3]([OH:43])=[O:4])(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:25][CH:26]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC1(C)[C@H](C(=O)NO)N(S(=O)(=O)c2ccc(-c3ccc(Br)cc3)cc2)CCS1(=O)=O
Reactant: OBO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=O
Solvent: C1COCCO1
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(-c3ccc(CO)cc3)cc2)[C@H]1C(=O)O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
(S)-4-(4-Iodophenyl-1-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxamide-O-Wang resin (15, Scheme 4) (5.0 g at 1 mmol/g loading, 5 mmol) was swelled in dioxane (40 mL). To this was added 4-hydroxymethylbenzene boronic acid (30 mL of a 0.5 M solution in dioxane/2.5 M aq. Na2CO3 [3 M equivalents relative to the boronic acid], 15 mmol). In a dry, oxygen free environment Pd(PPh3)4 (200 mg) was added, and the mixture was stirred while at 75° C. for 48 hours. Filtration and subsequent resin washing three times with alternating CH2Cl2 (20 mL) followed by THF (20 mL) gave the (S)-4-(4′-hydroxymethyl-biphenyl-4-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxamide-O-Wang resin.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].OS(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>C1CCCCC1.ClCCl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:53][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.1 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in cyclohexane (0.8 ml) and dichloromethane (0.4 ml) was added 2,2,2-benzyltrichloroacetimidate at 0° C. followed by triflic acid. The reaction was allowed to warm to room temperature and stir for 1.5 hours after which time it was poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic extracts were dried (MgSO4) and concentrated and the crude material was purified by column chromatography on silica gel eluting with 65% hexane:35% ethyl acetate to give the desired product (22 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[C:3]([O:18][C@@H:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][C@H:21]2[CH3:33])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1O
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a mixture of 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (193 mg, 0.729 mmol), tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate (173 mg, 0.802 mmol) and triphenylphosphine (230 mg, 0.875 mmol) in THF (2.0 mL) was added DEAD (0.129 mL, 0.875 mmol). The resulting mixture was stirred at room temperature overnight and then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield trans-tert-butyl 4-(5-chloro-1-(4-cyano-3-fluorophenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)-3-methylpiperidine-1-carboxylate (183.5 mg, 50.1%) as an orange solid. 1H NMR (400 MHz, DMSO): 6 ppm 7.99-8.15 (m, 2H), 7.80 (dd, J=10.55, 1.76 Hz, 1H), 7.55 (dd, J=8.35, 1.76 Hz, 1H), 6.21 (s, 1H), 4.67-4.84 (m, 1H), 3.52 (app br s, 2H), 3.18 (app br s, 2H), 1.99 (app br s, 1H), 1.82 (app br s, 1H), 1.62-1.73 (m, 1H), 1.40 (s, 9H), 0.90 (d, J=7.03 Hz, 3H). MS (ESI) 406 (M−56+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([OH:26])=O)=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:45]2C=CC=CC=2N=N1.CN.O1CCCC1>CN(C=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[S:20][C:21]([C:24]([NH:41][CH3:45])=[O:26])=[CH:22][N:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC1Cc2ccc(-c3ncc(C(=O)O)s3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1cnc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1,3-thiazole-5-carboxylic acid (15.0 mg, 0.0322 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.2 mg, 0.0322 mmol) and 2.0 M of methylamine in tetrahydrofuran (0.100 mL, 0.200 mmol) in DMF (1.0 mL) was stirred at r.t. for 2 h., and was diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=479.1.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([S:23]([O-:25])=[O:24])=[C:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].[Li+].Cl[N:33]1C(=O)C[CH2:35][C:34]1=O.[OH2:40]>ClCCl.Cl>[OH:40][CH2:35][CH2:34][NH:33][S:23]([C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:25])=[O:24]
Reactant: O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)[O-])c(Cc3cccc4ccccc34)sc21
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Agent: [Li+]
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)NCCO)c(Cc3cccc4ccccc34)sc21
Reaction time: 1 h

Procedure:
N-Chlorosuccinimde (52 mg) was added to a rapidly stirred suspension of lithium 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfinate (200 mg) in dichloromethane (8 ml) and 0.22M hydrochloric acid (9 ml). After 1 hour, further N-chlorosuccinimide (26 mg) was added. After 1 hour, water (30 ml) and dichloromethane (30 ml) were added and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic extracts were treated with ethanolamine (0.071 ml). After 30 minutes, the solution was washed with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ether to give the title compound (120 mg) as a foam.
Reaction SMILES: [C:1]1([C:5](=[CH:7][C:8](=[C:10]([CH:12]=1)[CH3:11])[CH3:9])[CH3:6])[CH:2]([NH2:4])[NH2:3].[C:13](Cl)(Cl)=[O:14]>>[N-:4]=[C:2]=[O:14].[N-:3]=[C:13]=[O:14].[C:1]1([C:5](=[CH:7][C:8](=[C:10]([CH:12]=1)[CH3:11])[CH3:9])[CH3:6])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C)c(C(N)N)cc1C
Product: Cc1cc(C)c(C)cc1C
Product: [N-]=C=O

Procedure:
The reaction of the anhydrous and catalyst-free solution of crude durene diamine with phosgene in conventional amounts (ca. 2 to 8 moles, preferably 3 to 6 moles of phosgene for each 1 mole of durene diamine) to form durene diisocyanate may be carried out by conventional cold-hot phosgenation. This means that a solution of phosgene in the organic solvent that was, for example, previously used is first added at a low temperature (from about 0 to 30° C.) to the phosgenation reactor, the durene diamine solution is mixed in, optionally while cooling. The resultant suspension is then heated to reflux and the reaction is completed under reflux, optionally with the addition of more phosgene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>C(#N)C>[Br-:10].[CH2:16]([N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:18]2([CH2:17][CH3:16])[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH:4]=1)[CH2:17][CH2:18][CH2:19][CH2:11][CH3:12]
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCCc1ccc2ccccc2c1
Reactant: CCBr
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCC[n+]1cn(C2(CC)C=Cc3ccccc3C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromethane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-(2-bromoethyl)naphthalene (9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, and the volatiles will be removed en vacuo resulting in the product.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12]O)=[CH:7][C:6]=1[CH3:14])(=[O:3])[CH3:2].[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][Br:15])=[CH:7][C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)Oc1c(C)cc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1c(C)cc(CBr)cc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
To a solution of commercially available 4-(hydroxymethyl)-2,6-dimethylphenyl acetate (1 g, 5.15 mmol) and perbromomethane (2.39 g, 7.21 mmol) in tetrahydrofuran (25 mL) was added triphenylphosphine (1.620 g, 6.18 mmol). The mixture was stirred at room temperature for 6 hours then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, hexane:ethyl acetate 4:1) to provide the title compound (1.05 g, 80% yield). MS (DCI/NH3) m/z 274 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([O-:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: O=C([O-])COc1cc2ccsc2c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2ccsc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7.5 g of ethyl[ (6,7-dichlorobenzo[b]thien-5-yl oxy]acetate, 15 g of potassium hydroxide pellets, 125 ml of ethanol and 125 ml of water is refluxed for 1 hour. Ethanol is removed under reduced pressure at 60° and the aqueous suspension is acidified with conc hydrochloric acid. The slurry is stirred at room temperature for 30 min. and extracted with ether (3×250 ml-portions). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an off-white crystalline mass. Recrystallization of the crude product from acetone-cyclohexane gives 6.5 g of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid as an off-white powder, mp 166°-167°.