Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[K+].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:27]=[S:28])[C:14]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reaction time: 2 h

Procedure:
To a cooled mixture of 2.1 g of 6-amino-2-tert-butyl-5-(4-methylpiperidin-1-yl)benzothiazole and 2.8 g of potassium bicarbonate in 20 ml of chloroform is added dropwise 1.6 g of thiophosgene in 5 ml of chloroform under stirring. The stirring is continued for 2 hours maintaining the temperature at 0°-2° . The solid is filtered and the filtrate is evaporated. The solid thus obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole, melting at 54°-58°.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:29](=[O:30])[N:16]([NH:19][CH2:20][CH2:21][C:23]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Example 269A (0.046 g, 0.10 mmol) in tetrahydrofuran (5 mL) and methanol (0.005 mL, 0.12 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.06 mL, 0.12 mmol). The reaction was stirred at 25° C. for 3 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 99:1 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (m, 3 H) 4.49 (m, 1 H) 5.90 (m, 1 H) 7.20 (d, J=8.09 Hz, 1 H) 7.27 (t, J=8.46 Hz, 2 H) 7.30 (m, 5 H) 7.54 (m, 2 H) 7.66 (d, J=8.09 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Br)cnc1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2,5-dibromo-3-nitropyridine (0.99 g, 3.5 mmol) in EtOAc (30 mL) was added tin(II) chloride dihydrate (4.0 g, 17.8 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 2 h, the reaction was cooled to rt and diluted with EtOAc, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as 2,5-dibromopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (1H, d, J=2.0 Hz), 7.27 (1H, d, J=2.3 Hz), 5.82 (1H, s).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[C@H:10]([C:21]([O:23][CH3:24])=[O:22])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reaction time: 24 h

Procedure:
Palladium hydroxide (20% on carbon, 1 g) was added to a solution of methyl (3S,4R)-1-benzyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 30 (10 g, 30 mmol) in ethanol (50 mL) at room temperature. The reaction mixture was hydrogenated at 50 psi for 24 hours and then filtered through Arbocel® washing with ethanol (50 mL). The solvent was removed in vacuo to give the desired compound as a colourless oil, 7.19 g (98%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][CH2:78]1>CN(C)C=O>[C:86]([O:85][C:83]([N:80]1[CH2:79][CH2:78][CH:77]([NH:76][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([CH2:31][CH3:32])[CH:24]=2)[CH2:82][CH2:81]1)=[O:84])([CH3:89])([CH3:88])[CH3:87]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.047 g (0.359 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0270 g (0.135 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0527 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-201) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH2:30][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CS(=O)(=O)N1CCCNCC1
Agent: Cl
Product: CS(=O)(=O)N1CCCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using General Procedure C (reductive amination) yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
Trifluoroacetic acid (10 mL) was added slowly to a cooled (0° C.) solution of N′-(2-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜5.3 mmol) in dichloromethane (10 mL), and the resulting solution was stirred at 0° C. for 10 min and then at room temperature for 3.5 h. The solvent was evaporated and dichloromethane (80 mL) was added. The solution was washed with water (4×20 mL) and brine (20 mL), dried (magnesium sulfate), filtered, and evaporated to give an orange foam. This was triturated with 10% ethyl acetate/hexane (25 mL) and the mixture was cooled in an ice-bath at 0° C. for 1 h. The solid was filtered off and dried to give (4R,7S)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (890 mg, 58%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl>C(Cl)Cl>[CH3:12][O:11][C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH3:13])[C:6]=1[CH:18]=[O:19]
Reactant: COC(Cl)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C)c(C=O)c(OC)c1OC
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A dry methylene chloride (100 ml) solution of 128 g (0.7 mol) of 3,4,5-trimethoxytoluene was dropwise added to a dry methylene chloride 500 ml solution of 112 g (0.84 mol) of aluminum chloride gradually under cooling with ice. The mixture was stirred at the same temperature for 45 minutes, a dry methylene chloride solution of 88.5 g (0.77 mol) of dichloromethyl methyl ether was dropwise added thereto gradually over a period of 2 hours. Stirring was conducted at the same temperature for 2 hours, and the mixture was gradually recovered to room temperature, followed by stirring at room temperature for one night. The reaction mixture was poured into 1 l of ice water, the methylene chloride phase was separated, and the aqueous phase was extracted with 200 ml of methylene chloride twice. The extract and the methylene chloride phase were combined together, sequentially washed with 200 ml of water, 200 ml of a saturated aqueous sodium bicarbonate solution and 200 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A seed for a crystal was inoculated into the residue, and the resulting crystal was collected by filtration, washed with hexane and air dried to obtain 128 g of 2,3,4-trimethoxy-6-methylbenzaldehyde (m.p. 55-57° C.).
Reaction SMILES: C1(S([CH:10]2[CH:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]3[CH2:25][CH2:26][CH:11]2[CH:12]=[CH:13]3)(=O)=O)C=CC=CC=1.[N+:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[C-:28].CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH2:33]([O:32][C:30]([C:29]1[NH:27][CH:28]=[C:15]2[C:10]=1[CH:11]1[CH2:26][CH2:25][CH:14]2[CH:13]=[CH:12]1)=[O:31])[CH3:34]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=S(=O)(c1ccccc1)C1C2C=CC(CC2)C1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
The reaction system of a mixed solution of 7.76 g (20 mmol) of the resultant 5,6-bis(phenylsulfonyl)-bicyclo[2.2.2]octa-2-ene and 50 ml of anhydrous tetrahydrofuran was replaced with nitrogen. Then, 2.425 ml (22 mmol) of ethyl isocyanoacetate were added to the solution, and the mixture was cooled to 0° C. Potassium t-butoxide (50 ml/1 M THF (tetrahydrofuran) solution) was dropped over 2 hours, and the whole was stirred at room temperature for 3 hours. After the completion of the reaction, dilute hydrochloric acid was added, and then the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, distilled water, and a saturated salt solution in this order, followed by drying with anhydrous sodium sulfate. The dried product was purified by means of silica gel column chromatography (chloroform) to yield ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (3.5 g, 16 mmol, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14](OCC)=[O:15])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH2:14][OH:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(c2ccc(Cl)cc2)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: OCC1=C(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of EXAMPLE 8B (1.6 g, 6.38 mmol) in ether (20 mL) was added LiAlH4 (1.2 g, 32 mmol). The mixture was stirred at room temperature for four hours. The mixture was acidified carefully with 5% HCl and extracted with ethyl acetate (100 mL×3) and washed with water, brine and dried over Na2SO4. After evaporation, the crude product was loaded on a column and eluted with 10% ethyl acetate in hexane to give title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.C([Li:16])CCC>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH:6]2[Li:16]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C)c2c1C=CC2
Solvent: C1CCOC1
Product: [Li]C1C=Cc2c(C)ccc(C)c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
38.2 g (265 mmol) of 4,7-dimethylindene were dissolved in 350 ml of tetrahydrofuran and the temperature of the solution was cooled to 0° C. Then, 165 ml of n-butyllithium (1.6M in hexane, 264 mmol) were added, dropwise for 2.5 hours. After having again heated up to room temperature and stirred the whole for 4 hours, a purple-red solution of 4,7-dimethylindenyl-lithium was obtained. This solution was cooled to -70° C. and treated, dropwise for 35 minutes, with 25.3 g of 1,2-dibromoethane (135 mmol) in 15 ml of tetrahydrofuran. After having heated up to room temperature, a slight yellow solution was obtained to which water was added. The organic phase was collected ed dried on Na2SO4. The solvent was then evaporated under vacuum and 20 g of product were obtained (yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
To a solution of methyl 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (694.5 mg, 1.50 mmol) in is tetrahydrofuran (4.0 mL) was added lithium tetrahydroborate (35.7 mg, 1.641 mmol) at 0° C. The reaction mixture was stirred at room temperature for 17 hrs. The starting material wasn't consumed completely. To the reaction mixture was added lithium tetrahydroborate (35.7 mg, 1.641 mmol) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The solvent was removed by concentration. The precipitate was collected by filtration and washed with water to give the title compound as a colorless solid (144.0 mg, 0.381 mmol, 93%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:15]([N:19]4[S:23](=[O:25])(=[O:24])[NH:22][C:21](=[O:26])[CH2:20]4)=[CH:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Cl[C:43]([O:45][CH3:46])=[O:44]>C1COCC1>[CH3:46][O:45][C:43](=[O:44])[NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][C:15]([N:19]4[CH2:20][C:21](=[O:26])[NH:22][S:23]4(=[O:25])=[O:24])=[C:14]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:13]=3)[CH:18]=2)[CH:4]=1
Reactant: COC(=O)Cl
Reactant: NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 5-[7-(3-aminomethylphenyl)-3-benzyloxynaphthalen-2-yl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.046 g, 0.097 mmol) and triethylamine (0.014 mL, 0.098 mmol) in THF (3 mL) at 0° C. is added methyl chloroformate (0.008 mL, 0.104 mmol). The reaction is stirred for 30 min and then quenched with water and extracted with CH2Cl2 (3×25 mL). The organic layers are combined and concentrated. The residue is purified via Biotage Sp1 eluting with 5-60% CH3CN/H2O to afford {3-[6-benzyloxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-benzyl}-carbamic acid methyl ester: (M−H)−=530.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.C([Li])CCC.[CH3:24][S:25]SC.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:18][O:17][C:5]1[CH:4]=[CH:3][C:2]([S:25][CH3:24])=[CH:16][C:6]=1[CH2:7][OH:8]
Reactant: CSSC
Reactant: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(SC)cc1CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a solution of Example 170A (2.91 g, 8.75 mmol) in 20 mL of tetrahydrofuran at −78° C. was added 1.6 M n-butyllithium in hexanes (7.1 mL, 11.4 mmol). The reaction was stirred at −78° C. for 10 min, then 1.5 mL of dimethyldisulfide was added. The reaction was warmed to ambient temperature and stirred for 2 h, then concentrated in vacuo. The residue was taken up in 50 mL of diethyl ether, then extracted with water (2×15 mL), 2 M NaOH(aq.) (1×15 mL), and brine (1×15 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. This was taken up in 15 mL of tetrahydrofuran and treated with 2.0 g (ca. 7 mmol) of tetrabutylammonium fluoride hydrate. The reaction was stirred at ambient temperature for 1 h, then concentrated in vacuo. The residue was taken up in 30 mL of diethyl ether, then extracted with water (2×10 mL), 2M NaOH(aq.) (1×10 mL), and brine (1×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to an oil. The product was purified via silica gel chromatography, eluting with a 20-40% ethyl acetate in hexanes gradient to give 1.23 g (76%) of the alcohol. The product was about 90% pure by 1H NMR analysis.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O-:22])([O-])=[O:20].[Cs+].[Cs+].CO>COCCOC.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>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([C:9]#[C:8][C:7]2[C:2]([C:14]3[CH:15]=[CH:10][C:11]([C:19]([OH:22])=[O:20])=[N:12][CH:13]=3)=[N:3][CH:4]=[N:5][C:6]=2[CH2:17][CH3:18])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: CCc1ncnc(-c2ccc(C(=O)O)nc2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized in analogy to general procedure GP4 starting from 1.2 g (4.63 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 1.0 g (5.6 mmol) 4-methoxycarbonyl-3-pyridyl boronic acid, 163 mg (0.23 mmol) bis-(triphenylphoshine)palladium(II) chloride, 7.0 mL (13.9 mmol) of an aqueous 2 M Cs2CO3 and 2 mL MeOH in 10 mL DME. The reaction mixture is stirred over night at 80° C. The reaction mixture is poured on water and washed with DCM. Aqueous 1 M HCl is added to the aqueous phase until pH 5 is reached. The precipitated product is filtered off and washed with water and methanol. After drying 290 mg (13%) of the desired product are obtained a solid material which is used for the next step without further purification.
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC(O[N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:86].[Na+].[Na+].[Na+].[Na+].[C:91]([CH2:94][CH2:95][CH2:96][CH2:97][C:98]1[CH:99]=[C:100](/[C:104](=[CH:129]\[CH:130]=[C:131]2\[N:132]([CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150])[C:133]3[C:138]([C:139]\2([CH3:141])[CH3:140])=[CH:137][C:136]([S:142]([O-:145])(=[O:144])=[O:143])=[CH:135][CH:134]=3)/[CH:105]=[CH:106]/[C:107]2[C:115]([CH3:117])([CH3:116])[C:114]3[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:120])=[O:119])[CH:113]=3)[N+:108]=2[CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])[CH:101]=[CH:102][CH:103]=1)([OH:93])=[O:92].[Na+].[Na+].[Na+]>>[CH3:117][C:115]1([CH3:116])[C:114]2[C:109](=[CH:110][CH:111]=[C:112]([S:118]([O-:121])(=[O:119])=[O:120])[CH:113]=2)[N:108]([CH2:122][CH2:123][CH2:124][S:125]([O-:128])(=[O:127])=[O:126])/[C:107]/1=[CH:106]/[CH:105]=[C:104](\[C:100]1[CH:101]=[CH:102][CH:103]=[C:98]([CH2:97][CH2:96][CH2:95][CH2:94][C:91]([O:93][N:78]2[C:82](=[O:83])[CH2:81][CH2:80][C:79]2=[O:84])=[O:92])[CH:99]=1)/[CH:129]=[CH:130]/[C:131]1[C:139]([CH3:140])([CH3:141])[C:138]2[C:133](=[CH:134][CH:135]=[C:136]([S:142]([O-:145])(=[O:144])=[O:143])[CH:137]=2)[N+:132]=1[CH2:146][CH2:147][CH2:148][S:149]([O-:152])(=[O:151])=[O:150].[Na+:86].[Na+:86].[Na+:86]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCCCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 15 was prepared analogously to compound 9 (Example 9), except that compound 14 is used as a starting material.
Reaction SMILES: [C:1](N)(=O)[C@H:2]([C@@H:4]([C:6](N)=[O:7])O)O.[C:11]1(O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>>[C:14]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([OH:7])=[CH:4][CH:2]=[C:1]2[C:13]=1[CH:12]=[CH:11][CH:20]=[CH:19]2
Reactant: Oc1cccc2ccccc12
Reactant: NC(=O)[C@@H](O)[C@H](O)C(N)=O
Product: Oc1ccc2ccccc2c1-c1cccc2ccccc12

Procedure:
On the other hand, 2.7 g of (+)-binaphthol (VII) ([α]D20, +21.0° (C=0.55, tetrahydrofuran)) which was obtained by silica gel chromatography of the filtrate obtained when the clathrate compound was separated and 2.19 g of (-)-(S,S)-tartaric acid diamide (X) were dissolved in the above-described mixed solvent, and thus-obtained solution was allowed to stand for 12 hours at room temperature. The crystallized crystal was recrystallized once to obtain 2.70 g of a clathrate compound (colorless prismatic crystal: mp, 150-151° C.; [α]D20, -43.9° (CHCl3)) containing (-)-tartaric acid diamide (X) and (+)-naphthol (XI) in a ratio of 1 : 1. The obtained crystal was subjected to column chromatography to obtain 1.48 g of (+)-binaphthol (VII) ([α]D20, +36.5° (C=1.3, tetrahydrofuran)).