Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:11]2[CH2:17][NH:16][C:15](=[O:18])[CH:14]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.CN(C)P(=O)(N(C)C)N(C)C.O>[C:1]1([CH:11]2[CH2:17][N:16]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:15](=[O:18])[CH:14]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[CH2:13][S:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NCC(c2cccc3ccccc23)SCC1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N2C(=O)c3ccccc3C2=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3.4 g of 2-(1-naphthyl)-5-oxo-6-phthalimidoperhydro-1,4-thiazepine [prepared as described in step (e) above] in a mixture of 34 ml of dimethylformamide and 10 ml of hexamethylphosphoric triamide were added dropwise 2.25 ml of t-butyl bromoacetate and then, bit by bit, 609 mg of a 55% w/w suspension of sodium hydride in oil at 0°-5° C., under a nitrogen stream. After this addition, the reaction mixture was stirred for 16 hours at room temperature. Ethyl acetate and water were then added to the reaction mixture. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvnet was distilled off. The residue was subjected to silica gel column chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to give 2.6 g of the title compound as crystals, melting at 211°-213° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:8][C:6]=2[N:7]=1.[F:24][C:25]1[C:30]([F:31])=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[NH:41][C:42](=[O:55])[NH:43][C:44]1[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:24][C:25]1[C:30]([F:31])=[C:29]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[N:11]=[CH:10][C:9]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)=[CH:8][C:6]=3[N:7]=2)[CH:28]=[CH:27][C:26]=1[NH:41][C:42](=[O:55])[NH:43][C:44]1[CH:54]=[CH:53][C:47]([C:48]([N:50]([CH3:52])[CH3:51])=[O:49])=[CH:46][CH:45]=1
Reactant: Cn1cc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cn1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ncc(-c5cnn(C)c5)cc4n3)c(F)c2F)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 10.9 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-7-(1-methyl-1H-pyrazol-4-yl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.1 g, 0.0003 mol), 4-(3-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-N,N-dimethyl-benzamide (0.16 g, 0.00036 mol), cesium carbonate (0.244 g, 0.00075 mol), toluene (7 mL), EtOH (7 mL), and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.0105 g, 0.000015 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3 h. To the cooled reaction mixture, ice cold water was added to obtain the solid. The crude product was obtained by the filtration of the solid. The crude product was purified by column chromatography using 60-120 silica gel and 4% MeOH in chloroform to isolate the product. The isolated product was washed with MeOH and filtered. The compound was further purified by prep TLC using 7% MeOH in chloroform to yield the title compound [0.02 g, 11%]. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (brs, 1H), 9.09 (d, J=2.0 Hz, 1H), 9.01 (brs, 1H), 8.53 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.14-7.97 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 4.49 (brs, 4H), 3.92 (s, 3H), 3.81 (brs, 1H), 2.96 (s, 6H). LC-MS (ESI): Calculated mass: 613.2; Observed mass: 614.2 (RT: 0.63 min).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.N(OCCC(C)C)=O>CN(C=O)C.C1COCC1>[CH2:10]([O:9][C:7]([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cncs1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 g, 0.29 mmol) in a mixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87 minutes to a stirred 41° C. solution of isoamyl nitrite (59 mL, 0.44 mol) in DMF (130 mL). A maximum temperature of 60° C. was observed during the exothermic addition. After another 40 minutes the THF was removed under vacuum at 45° C. The concentrated DMF solution was cooled to 25° C. and diluted with toluene (420 mL) and water (440 mL). The toluene layer was extracted with 3×120 mL water, then dried with Na2SO4 (50 g) for 1 hour. After filtration the toluene layer was stripped on a rotary evaporater at 50° C. bath temperature, then on a vacuum pump at 21° C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1H NMR (CDCl3) δ8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t, 3H). 13C NMR (CDCl3) δ161.0, 157.9 148.6, 129.8, 61.6, 14.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-])=O.[OH-].[Na+]>Cl.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1c2ccccc2c2cc(N)ccc21
Temperature: 0 °C
Yield: 82.8 %

Procedure:
A solution of 10.2 g of 3-nitro-N-ethylcarbazole (42.5 mmol) and 38.4 g of stannous chloride dihydrate (170 mmol) in 100 ml of concentrated hydrochloric acid was heated for 3 hours at 92° C. The ice cooled solution was (cautiously) made basic by partial addition of a solution of 75 g sodium hydroxide in 150 ml of water. The product was filtered off and washed with the above base solution, followed by copious amounts of water, and then air dried. Vacuum drying and recrystallization from pyridine/water gave 7.4 g light-green needles (82% yield) mp b 109°-11° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23](=[S:25])[NH2:24])=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH:29](OCC)OCC>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:22][C:21]([C:23]3[S:25][CH:28]=[CH:29][N:24]=3)=[C:20]([CH3:26])[CH:19]=2)[C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1C(N)=S
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)[nH]c1-c1nccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution (3 mL) of 5-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-3-methyl-1H-pyrrole-2-carbothioamide (120 mg) in N,N-dimethylacetamide was added 2-bromo-1,1-diethoxyethane (125 mg), and the mixture was stirred at 60° C. for 2 hr, then at 100° C. for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (60 mg, yield 47%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 415 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:5])C.[OH-].[K+]>CO.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:10]2[S:9][CH:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:13]=1
Reactant: CCOC(=O)c1ncsc1Nc1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ncsc1Nc1cccnc1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
A solution of 5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (2.90 g, 11.63 mmol) in methanol (24.00 ml) was treated at room temperature with a solution of KOH (1.95 g, 34.90 mmol) in water (18 ml) and stirred at 65° C. for 2 h 45 min. The methanol was evaporated and the residual slurry acidified to pH 5 with 1N HCl. The mixture was sonicated for 15 minutes, then filtered washing with water. The solid was dried under high vacuum overnight, yielding 5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (2.37 g, 92%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:21]1[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=1)[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[O:25])=[O:7].[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C@H:51]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52]1)=[O:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:44][O:45][CH2:46][CH2:47][NH:48][C:49]([C@H:51]1[CH2:56][CH2:55][CH2:54][N:53]([CH2:2][C:3]2[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=2)[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[C:21]2[CH:22]=[C:23]([CH:38]=[CH:39][N:40]=2)[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:25])=[O:7])[CH2:52]1)=[O:50]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)c2)c1
Reactant: COCCNC(=O)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNC(=O)[C@H]1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 20 mg of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a, 8.8 mg of (S)—N-(2-methoxyethyl)piperidine-3-carboxamide and 13.7 mg of K2CO3 in 0.33 mL of DMF was stirred for 2 h. The product was isolate by preparative reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 23 mg of product. MS (ES, m/z) 757.3 [M+H]+
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([O:9][C@@H:10]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[C:11]([O:13][CH2:33][CH2:32][Si:31]([CH3:36])([CH3:35])[CH3:30])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Reactant: C[Si](C)(C)CCO
Agent: O=C(Cl)C(=O)Cl
Product: CC(C)(C)c1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)OCC[Si](C)(C)C)cc1

Procedure:
The target compound (16.0 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(e) using the above carboxylic acid (13.3 g), oxalyl chloride (18.45 ml) and 2-trimethylsilylethanol (30.3 ml).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]Br)=[CH:10][C:4]=2[O:3]1.[C-:14]#[N:15].[K+].[Br-].[K+]>O>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:14]#[N:15])=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(CBr)cc2O1
Reactant: [C-]#N
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Yield: 65.8 %

Procedure:
To a solution of 2,2-difluoro-5-bromomethyl-1,3-benzodioxole (41.0 g) in absolute alcohol (160 ml) at 60°-70° C a hot solution of potassium cyanide (22.1 g, 0.34 mole) in water (30 ml) is added. There is a slight exotherm and within 5 minutes potassium bromide separates out of the reaction mixture. The reaction mixture is refluxed for 1.5 hours, cooled and added to ice-water. The mixture is extracted with ether (3×100 ml), the combined extracts are washed with water (2×50 ml), dried over sodium sulfate and evaporated to afford a dark oil. Vacuum distillation yields 21.2 g of product (64% yield); b.p. 64°-67° C (at 0.03 mm); i.r. (neat) 2255 cm-1 ; nmr (CCl4) δ 3.68 (S, 2H), 7.00 (S, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:20]=[C:19]3[C:11]([N:12]4[C:17](=[CH:18]3)[C:16](=[O:21])[NH:15][CH2:14][CH2:13]4)=[N:10][CH:9]=2)[CH2:3][CH2:2]1.O.[CH:23]1([CH:26]=O)[CH2:25][CH2:24]1.C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:23]1([CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:20]=[C:19]4[C:11]([N:12]5[C:17](=[CH:18]4)[C:16](=[O:21])[NH:15][CH2:14][CH2:13]5)=[N:10][CH:9]=3)[CH2:5][CH2:6]2)[CH2:25][CH2:24]1
Reactant: O=C1NCCn2c1cc1cc(OC3CCNCC3)cnc12
Reactant: O=CC1CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1NCCn2c1cc1cc(OC3CCN(CC4CC4)CC3)cnc12
Temperature: 55 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
To a solution of 0.40 g (1.40 mmol) 7-(piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one in 8 mL tetrahydrofuran, 30 μL (30 μg, 1.67 mmol) water, 0.16 mL (0.15 g, 2.11 mmol) cyclopropanecarboxaldehyde, 0.24 mL (0.25 g, 4.2 mmol) acetic acid and 2.1 mL (1.93 g, 2.1 mmol) sodium cyanoborohydride (1M solution in tetrahydrofuran) were added successively and the reaction mixture was stirred for 18 hours at 55° C. After cooling to room temperature the reaction was poured on 10% aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.19 g (40%) of the desired compound as a white solid.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:8]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)[N:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]>C(O)(=O)C>[NH2:3][C:4]1[N:8]([C:9]2[C:13]([Br:1])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)[N:7]=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: BrBr
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Solvent: CC(=O)O
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)c(Br)c1OC(F)F
Reaction time: 0.5 h

Procedure:
8.3 g (0.052 mol) Bromine was added dropwise at room temperature to 13 g (0.047 mol) 5-amino-4-nitro-1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)pyrazole dissolved in 260 ml acetic acid and the mixture stirred for 30 minutes. It was then concentrated and the residue taken up in the ethyl acetate and shaken with 5% aqueous sodium hydrogen carbonate. The phases were separated and the organic phase dried over magnesium sulfate. This was concentrated and the residue purified by silica gel column chromatography (hexane/ethyl acetate 3:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.ClCCl.C([O-])(=O)C.[K+].[C:38]([O:42][C@@H:43]([C:49]1[C:64]([CH3:65])=[CH:63][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]=[C:58](Cl)[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:66]1[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>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.O>[C:38]([O:42][C@@H:43]([C:49]1[C:64]([CH3:65])=[CH:63][C:52]2[N:53]=[C:54]([C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:2]4[CH:3]=[C:4]5[CH:10]=[C:9]([CH3:11])[NH:8][C:5]5=[N:6][CH:7]=4)[CH:57]=3)[S:55][C:51]=2[C:50]=1[C:66]1[CH:67]=[CH:68][C:69]([Cl:72])=[CH:70][CH:71]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2cc(Br)cnc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5[nH]c(C)cc5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.284 mmol) in dioxane (3 mL) was added bis(pinacolato)diboron (87 mg, 0.341 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (23 mg, 0.028 mmol), potassium acetate (84 mg, 0.852 mmol). The mixture was degassed and heated at 100° C. for 2 h. The mixture was cooled, and then added (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (100 mg, 0.189 mmol), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.019 mmol), K2CO3 (131 mg, 0.948 mmol) and water (1 mL, degassed). The reaction mixture was heated at 110° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C35H33ClN4O3S: 625.2 (M+H+); Found: 625.3 (M+H+).
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9](S(C)(=O)=O)[S:8][N:7]=1.[CH3:17][O-:18].[Na+].O>CO>[I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[C:10]([C:11]#[N:12])=[C:9]([O:18][CH3:17])[S:8][N:7]=1
Reactant: CS(=O)(=O)c1snc(OCC#CI)c1C#N
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1snc(OCC#CI)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
3.6 Grams of 3-(3-iodo-2-propynyloxy)-4-cyano5-methylsulfonylisothiazole synthesized in Example 2 was dissolved in 30 ml of methanol, 0.6 g of sodium methoxide was added thereto, and then the reaction solution was stirred at room temperature for 4 hours. Water was added to precipitate crystals, which were then collected by filtration, washed with water, dried and recrystallized from ether. Thus, 2.4 g of crystals having a melting point of 159° to 160° C. (yield 78%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.CCCCCC>C(O)C.C1(C)C=CC=CC=1.C(OCC)C>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:29]=[CH:30][C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[S:58])=[CH:3][C:4]=3[F:31])[N:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (110 mg) in ethanol (2.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (101 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 3.06 ml) was added to the reaction mixture, followed by stirring at room temperature for 2 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (10 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=20:1, then 10:1). Fractions containing a target compound were concentrated to give a solid, which was suspended in diethyl ether:hexane=1:1. The solid was filtered off, and washed with diethyl ether to provide the titled compound (25.3 mg, 16.3%) as pale yellow powder.
Reaction SMILES: [Li+].[OH-].[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]3[CH2:18][C@@H:19]([CH2:32][C:33]([O:35]C)=[O:34])[C:20](=[O:31])[N:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][C:16]=3[CH:15]=2)[CH:8]=[CH:7][CH:6]=1>C1COCC1.O>[CH3:3][NH:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]3[CH2:18][C@@H:19]([CH2:32][C:33]([OH:35])=[O:34])[C:20](=[O:31])[N:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22][C:16]=3[CH:15]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CNc1cccc(CCOc2ccc3c(c2)CN(CCc2ccccc2)C(=O)[C@H](CC(=O)OC)C3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cccc(CCOc2ccc3c(c2)CN(CCc2ccccc2)C(=O)[C@H](CC(=O)O)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
1.0N LiOH (0.62 mL, 0.62 mmole) was added to a solution of methyl (S)-8-[2-[6-(methylamino)pyridin-2-yl]ethoxy]-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (250 mg, 0.51 mmole) in THF (2.5 mL) and H2O (1.9 mL) at 0°0 C., and the reaction was allowed to stir at RT for 18 hr. The mixture was washed with Et2O (2×5 mL) then a mild vacuum was applied to remove residual organic solvents. The aqueous layer was passed through a 0.45 μm Acrodisk filter then was carefully acidified to pH 6 using 10% HCl in H2O at 0° C. The precipitate was collected, washed with H2O, and dried under vacuum at 50° C. to give the title compound (134 mg, 55%) as a white solid: MS (ES) m/e 474 (M+H)+. Anal. Calcd for C28H31N3O4.0.75 H2O: C, 69.05; H, 6.73; N, 8.63. Found: C, 69.23; H, 6.59; N, 8.55.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][CH3:27]>CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14])=[CH:4][C:3]=1[O:17][CH2:25][CH2:26][CH3:27]
Reactant: CCCI
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C

Procedure:
As described in General Procedure D-1, 7-bromo-4,4-dimethyl-6-hydroxy-1-isopropyl-3,4-dihydronaphthalene (Compound A-30, U.S. Pat. No. 6,613,917, 0.100 g, 0.339 mmol), potassium carbonate (140 mg) and 1-iodopropane (0.331 mL, 3.39 mmol), were reacted in acetone (3 mL) to produce the title compound as a clear oil after purification by flash column chromatography (silica gel, 98:2 hexane/ethyl acetate).