Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].[C:6]1([CH3:33])[CH:11]=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=C[CH:7]=1.[Cl:34][C:35]1[CH:36]=[C:37]([C:42]([NH:48][CH3:49])([CH2:45][CH:46]=[CH2:47])[CH2:43][OH:44])[CH:38]=[CH:39][C:40]=1[Cl:41]>C(OCC)(=O)C>[C:6]([O:2][C:1](=[O:4])[N:48]([C:42]([C:37]1[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=1)([CH2:43][OH:44])[CH2:45][CH:46]=[CH2:47])[CH3:49])([CH3:33])([CH3:11])[CH3:7]
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Reactant: C=CCC(CO)(NC)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCC(CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate (650 mL) were added to 2-(3,4-dichlorophenyl)-2-methylamino-4-pentenol (+)-di-p-toluoyl-D-tartrate (84.8 g). The insoluble matter was passed through Celite, followed by washing with ethyl acetate. The filtrate was partitioned. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (250 mL). Di-tert-butoxydicarbonate (30.5 g) was added to the resultant solution, followed by stirring at 100° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified through silica gel column chromatography (n-hexan:ethyl acetate=8:1 to 3:1), to thereby give the title compound (45.3 g, 99%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: COc1ccccc1CN
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1CNC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-methoxybenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 46 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[C:33]#[CH:34].CN(C=O)C>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][N:35]4[CH2:36][CH2:37][S:38](=[O:42])(=[O:41])[CH2:39][CH2:40]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCN3CCS(=O)(=O)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-propargylthiomorpholine-1,1-dioxide (103.8 mg). Anhydrous DMF (18 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and further purified by HPLC. The product is recrystallized from hot acetonitrile to afford 86.1 mg (27%) of the desired product as a white solid.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11](Br)[CH:10]=[C:9]([Br:14])[CH:8]=1.[CH3:15][S:16]SC.[Cl-].[Na+]>CCOCC.O1CCCC1.C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[C:11]([S:16][CH3:15])[CH:10]=[C:9]([Br:14])[CH:8]=1
Reactant: CSSC
Reactant: Brc1cc(Br)cc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.5M solution of n-butyllithium (42 mL; 0.105M) was added over 25 mins. to a vigorously stirred suspension of 1,3,5-tribromobenzene (31.5 G; 0.1M) in 1.6 L of anhydrous ether and 400 mL of anhydrous tetrahydrofuran under nitrogen at -78°. After stirring the mixture 30 minutes, 2 equivalents of dimethyldisulfide was added dropwise. The resulting mixture was stirred at R.T. overnight. 150 mL of sat'd sodium chloride solution was cautiously added. 500 mL of ethyl acetate was added. The organic phase was separated, and dried over anhyd. magnesium sulfate. Solvent removal gave a crude product, which was purified on silica gel using hexane as solvent. The desired product was isolated and distilled at 107°-110°/~1 mm to give 18 G of 3,5-dibromothioanisole as a colorless liquid, which slowly solidified on standing.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].[C:7]([CH:10]1[CH2:14][CH2:13][O:12][C:11]1=O)(=O)[CH3:8].Cl.P(Cl)(Cl)([Cl:19])=O>O.CC1C=CC=CC=1>[Cl:19][CH2:13][CH2:14][C:10]1[C:11](=[O:12])[N:3]2[CH:4]=[CH:5][S:1][C:2]2=[N:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nccs1
Reactant: CC(=O)C1CCOC1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2sccn2c(=O)c1CCCl
Reaction time: 2 h

Procedure:
A mixture of 50 parts of 2-thiazolamine, 76 parts of 3-acetyl-4,5-dihydro-2(3H)-furanone, 1.2 parts of concentrated hydrochloric acid and 270 parts of methylbenzene was stirred and refluxed for 2 hours using a water-separator. The reaction mixture is cooled and 340 parts of phosphoryl chloride were added at a temperature between 20° and 30° C. The whole was heated slowly to 100°-110° C. and stirring was continued for 2 hours at this temperature. The reaction mixture was evaporated and the residue was poured onto a mixture of crushed ice and ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 1,1'-oxybisethane, yielding 36 parts of 6-(2-chloroethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (intermediate 172).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:34])[N:17]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH:31]1([CH2:30][N:17]2[C:16](=[O:34])[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)=[N:18]2)[CH2:33][CH2:32]1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(-c2cc(CN3CCNCC3)c(=O)n(CC3CC3)n2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazine-3-one (220 mg, 0.47 mmol) was dissolved in ice-cold trifluoroacetic acid (2 mL), and at the same temperature, the mixture was stirred for 15 minutes. Water (10 mL) was added to the reaction mixture. The mixture was alkalinized with potassium carbonate and extracted twice with chloroform (20 mL). The extracts were washed with brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was recrystallized from chloroform-hexane to yield the title compound as pale yellow prisms (120 mg, 69.2%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[BH4-].[Na+]>C(O)C>[Cl:1][CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4]
Reactant: O=C(CCl)c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CCl)c1ncccn1
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
2-Chloro-1-pyrimidin-2-ylethanone (6.15 g, 39.3 mmol) was dissolved in ethanol (125 ml) and CeCl3.7H2O (14.64 g, 39.3 mmol) was added. Stirring was continued for 10 min then sodium borohydride (1.49 g, 39.3 mmol) was added over 2 min. After 1 hr the solid was filtered and the filtrate evaporated. Sat. ammonium chloride solution (25 ml) was added followed by brine (250 ml) and the mixture adjusted to pH3-4 with 1N.HCl. Extraction with ethyl acetate (3×250 ml) afforded an amber oil which was chromatographed over silica gel (150 g) to give the product as a pale yellow oil (3.85 g) Physical characteristics are as follows: Anal. Found: C, 45.08; H, 4.47; N, 17.46.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH2:19](O)CCCC.IC1C(C2C3CCN(CC3)C2)=NN(COCC[Si](C)(C)C)C=1.CCO>CCO.C(OCC)(=O)C.C(N(CC)CC)C.CCO.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[C:7]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:19]
Reactant: CCCCOc1c[nH]nc1C1CN2CCC1CC2
Reactant: CCCCCO
Agent: C[Si](C)(C)CCOCn1cc(I)c(C2CN3CCC2CC3)n1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCOc1c[nH]nc1C1CN2CCC1CC2

Procedure:
Compound 52C was prepared following the procedure as described for the synthesis of compound 52A (see Scheme 10) using pentanol (25 ml) and 3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (50), (2 g, 4.61 mmol). Work-up and flash chromatography (gradient EtOH to EtOH/triethylamine 300/1) followed by a second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51C as an oil (0.46 g, 15%). LCMS (method B); Rt: 3.30 min, ([M+H]+=394).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17]C)=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[CH2:20][C:21]([O:23]C)=O.[NH2:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH2:31]>>[O:17]=[C:15]1[NH:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26][NH:25][CH2:20][C:21](=[O:23])[NH:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)CBr
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: NCCNCCN
Product: CC(C)(C)OC(=O)NCCCCC1NC(=O)CNCCNCCNC1=O

Procedure:
DOTA-alkyl-biotin was synthesized following the procedure of Takenouchi et al. (J. Organic Chem. 58:1955-1958, 1993) starting with the compound H-Lys(Boc)-OMe (Bachem, E-1620). H-Lys(Boc)-OMe was treated stepwise with methyl bromoacetate and diethylenetriamine to obtain tert-butyl 4-(3,12-dioxo-1,4,7,10-tetraazacyclododecan-2-yl)butylcarbamate. Borane-THF complex was used to reduce the carboxylic amides followed by trifluoroacetic acid Boc deprotection to obtain 4-(1,4,7,10-tetraazacyclododecan-2-yl)butan-1-amine. This compound was subsequently reacted with biotin-xx, SSE (Invitrogen, B-6352) in DMSO with a 10 fold molar excess of triethylamine for 3 hours vortexing at room temperature. In all synthesis steps compounds were purified by HPLC and confirmed by mass spectrometry with a Waters (Milford, Mass.) LCT electrospray time-of-flight (ES-TOF) liquid chromatography mass spectrometry (LC/MS) or by MALDI-TOF as described above.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C@H:9]1[O:14][C@@H:13]([O:15][C@@H:16]2[CH2:32][C@:31]3([OH:33])[C@@:19]([CH:42]=[O:43])([C@@H:20]4[C@@H:28]([CH2:29][CH2:30]3)[C@:27]3([OH:34])[C@@:23]([CH3:41])([C@@H:24]([C:35]5[CH2:40][O:39][C:37](=[O:38])[CH:36]=5)[CH2:25][CH2:26]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)[CH2:12][C@H:11]([OH:44])[C@@H:10]1[OH:45].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][CH:9]1[O:14][CH:13]([O:15][CH:16]2[CH2:32][C:31]3([OH:33])[C:19]([CH2:42][OH:43])([CH:20]4[CH:28]([CH2:29][CH2:30]3)[C:27]3([OH:34])[C:23]([CH3:41])([CH:24]([C:35]5[CH2:40][O:39][C:37](=[O:38])[CH:36]=5)[CH2:25][CH2:26]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)[CH2:12][CH:11]([OH:44])[CH:10]1[OH:45]
Reactant: C[C@H]1O[C@@H](O[C@H]2CC[C@]3(C=O)[C@H]4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)[C@@H]4CC[C@]3(O)C2)C[C@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C1CCCCC1
Solvent: C1COCCO1
Product: CC1OC(OC2CCC3(CO)C4CCC5(C)C(C6=CC(=O)OC6)CCC5(O)C4CCC3(O)C2)CC(O)C1O
Reaction time: 1 h

Procedure:
1.5 g. cyclohexanone-helveticoside are dissolved in 20 ml. of 80% aqueous dioxane and treated dropwise over a period of 1 hour with a solution of 0.35 g. sodium borohydride in 20 ml. of 75% dioxane. The reaction mixture is stirred for 1 hour, after which no more cyclohexanone-helveticoside can be detected. The solution is adjusted to pH 7 with dilute sulfuric acid, and the dioxane is evaporated under reduced pressure in a rotating evaporator. The aqueous phase is extracted repeatedly with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatographically over silica gel, using chloroform as solvent. Yield: 750 mg. cyclohexanone-helveticosol. Melting point: 155°-164°C;[α D20 ] (C = 1, chloroform) : +23°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[CH:11]=[C:12]([CH3:31])[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=4)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[CH:11]=[C:12]([CH3:31])[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:26][CH:25]=4)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2)CC1
Yield: 60.9 %

Procedure:
Using pyrrolidin-2-one (94 mg) and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (246 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[OH:11][CH2:12][C:13]([CH3:27])([CH3:26])[CH2:14][NH:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH2:14][C:13]([CH3:26])([CH3:27])[CH2:12][OH:11])=[CH:20][CH:21]=2)[N:3]=1
Reactant: CC(C)(CO)CNS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cnc(Cl)nc1N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(CO)CNS(=O)(=O)c1ccc(Nc2ncc(C#N)c(N)n2)cc1
Yield: 51.2 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (150 mg, 0.97 mmol), 4-[N-(3-hydroxy-2,2-dimethylpropyl)sulphamoyl]aniline (Method 4; 274 mg, 1.07 mmol) in NMP (5 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool, was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried and the solvent removed by evaporation, the residue was triturated with ether and the product collected by filtration to give the title compound (187 mg, 52%). NMR: 0.72 (s, 6H), 2.52 (d, 2H), 3.08 (d, 2H), 4.40 (t, 1H), 7.19 (t, 1H), 7.60 (s, 1H), 7.64 (d, 2H), 7.96 (d, 2H), 8.40 (s, 1H); m/z 375 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:25](=[O:27])[NH2:26])[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18](=[N:17][CH:16]=2)[N:19]([C:25]([NH2:26])=[O:27])[CH2:20][CH2:21][CH2:22]3)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
[5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) is dissolved in 5.0 mL of DCM and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 1 hr and the solvent is removed in vacuo. The residue is dissolved in MeOH and filtered through a StratoSpheres SPE cartridge (PL-HCO3 MP SPE) to remove the acid. The filtrate is then concentrated to give 75 mg of 6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide which is used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20](SC#N)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.Cl.[F:35][C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[O:42][CH2:41][CH2:40][C@H:39]2[NH2:47].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:47][C@H:39]2[C:38]3[C:43](=[C:44]([F:46])[CH:45]=[C:36]([F:35])[CH:37]=3)[O:42][CH2:41][CH2:40]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1
Reactant: N[C@@H]1CCOc2c(F)cc(F)cc21
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cc(F)cc43)n2)c(OC)c1
Reaction time: 24 h
Yield: 67.8 %

Procedure:
A partial suspension of 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile (415 mg) in 40 mL of acetonitrile was treated with a solution of (R)-6,8-difluorochroman-4-amine HCl salt (320 mg) in DMSO (10 mL) followed by potassium carbonate (1.0 g). The mixture was stirred for 24 hours, and then diluted with EtOAc (200 mL). The mixture was washed once with saturated aqueous ammonium chloride (200 mL) and 3 times with saturated aqueous NaCl (200 mL each). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (20→40% EtOAc/hexanes) provided 358 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C:12](=[O:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.CCOCC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C@@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1.[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@:9]45[CH2:22][C@H:10]4[CH2:11][C@H:12]([OH:21])[C@:13]5([CH2:15][CH2:16]3)[CH3:14])[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C[C@@H]3C[C@]312
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)C[C@@H]3C[C@]312
Reaction time: 1.5 h

Procedure:
100 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5-(10)-triene-17-one dissolved in 12 ml of absolute tetrahydrofuran are mixed with 100 mg of lithium aluminum hydride at 0° C. and set aside for 1.5 hours at room temperature. After adding ethyl acetate and ether the product is washed with saturated aqueous ammonium chloride solution and water, and the organic layer is separated, followed by drying with sodium sulphate and evaporating under vacuum. After preparative layer chromatography on silica gel (mobile phase: benzene/acetone/methanol 45:5:1) the residue yields 60 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5(10)-triene-17α-ol and 26 mg of 3-methoxy-14α,15α-methylene-estra-1,3,5(10)-triene-17β-ol.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[CH:14]=[N:13][CH:12]=[CH:11]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C-:16]#[N:17].[K+].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.O>[C:16]([CH:14]1[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:11]=[CH:12][N:13]1[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])#[N:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(-n2cccc2)c2cnccc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2C=Cc3cccc(-n4cccc4)c3C2C#N)cc1
Yield: 71.9 %

Procedure:
8-(Pyrrol-1-yl)isoquinoline (293 g.) and potassium cyanide (295 g.) are dissolved in a mixture of methylene chloride (880 cc.) and water (880 cc.) and the solution stirred at a temperature of between 0° and 5° C. After adding a solution of toluene-p-sulphonyl chloride (575 g.) in methylene chloride (880 cc.) over the course of 45 hours, decanting and then washing the organic solution with water, a solid brown residue is obtained. After recrystallisation from acetonitrile (750 cc.), this crude product yields 1-cyano-8-(pyrrol-1-yl)-2-toluene-p-sulphonyl-1,2-dihydroisoquinoline (407 g.) melting at 160° C.