Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH2:16]3)=[N:11][C:10]2=[O:28])=[CH:6][CH:5]=1.[H][H]>[Pd].C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[N:11][C:10]2=[O:28])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1nc(N2CCC(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 87.7 %

Procedure:
A methanol (1 mL) solution of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (30 mg, 0.08 mmol) synthesized in Synthesis Example 112 and palladium-activated carbon (3 mg) was stirred in a hydrogen atmosphere at room temperature for 1 day and at 80° C. for 7 hours. To the resultant mixture, chloroform was added and the resultant mixture was stirred further for 1 day. After the completion of the reaction, the reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (28 mg, yield: 92%).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:55])([C:51]([F:54])([F:53])[F:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50])[C:38]([O:40]CC)=[O:39]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH:37]([CH2:36][CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:55])[C:51]([F:52])([F:53])[F:54])[C:38]([OH:40])=[O:39])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16].Cl>C(O)(C)C.O>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: C=CC(=O)OC1CCCCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: C=Cc1ccc(O)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
130.5, Gram of poly(p-tert-butoxystyrene/cyclohexyl acrylate) was suspended in isopropanol, and 30 mL of concentrated hydrochloric acid was added to the suspension. This mixture was stirred at 70 to 80° C. over 4 hours and after cooling, the reaction solution was poured in 1,500 mL of water to precipitate the reaction product. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure. In this way, 85.5 g of poly(p-hydroxystyrene/cyclohexyl acrylate) was obtained as a white powder crystal.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.O.O.O.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>>[O:11]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: C1CCC2OC2C1
Agent: [Na+]
Solvent: O
Product: OC1CCCCC1Oc1ccccc1
Temperature: 25 °C

Procedure:
Cyclohexene oxide (10 g, 0.102 mol) was added dropwise to an aqueous solution of sodium phenoxide trihydrate (31.6 g, 0.186 mol; 250 mL). The mixture was refluxed overnight, cooled to room temperature, and a precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate. The organic phase was washed with 1 M NaOH, brine, dried (over MgSO4), and concentrated to give solid 2-phenoxy-cyclohexanol (a compound of general Formula II) (13.84 g, 70%). The melting point of this compound was determined to be 79-80° C. 1HNMR (CDCl3 ): δ7.3 (m, 2H), 6.9 (m, 3H), 4.0 (m, 1H), 3.7 (m, 1H), 2.1 (m, 2H), 1.8 (m, 4H), 1.4 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][CH:12]3[CH:8]([C:9](=[O:17])[NH:10][C:11]3=[O:16])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][CH3:19].[CH2:20](O)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:20]([N:10]1[C:9](=[O:17])[CH:8]2[CH:12]([CH2:13][CH2:14][C:15]3[C:3]([O:2][CH3:1])=[C:4]([O:18][CH3:19])[CH:5]=[CH:6][C:7]=32)[C:11]1=[O:16])[CH3:21]
Reactant: CCO
Reactant: COc1ccc2c(c1OC)CCC1C(=O)NC(=O)C21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1C(=O)C2CCc3c(ccc(OC)c3OC)C2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
A solution of thee compound of example 3 (1.5 g, 5.8 mmole), absolute ethanol (0.42 mL, 7.3 mmole), triphenylphosphine (1.5 g, 5.8 mmole), and dry THF (9.8 mL) was stirred under N2 at 15° C. as diethyl azodicarboxylate (0.92 mL, 5.8 mmole) was added dropwise. The reaction mixture was stirred at room temperature for 18 hrs., then the crude reaction mixture was chromatographed on silica gel, eluting with CH2Cl2 containing 0.5% EtOH to obtain 0.96 g yellow solid (57%); M+ 289.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:23])[CH2:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:24]
Reactant: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
A stirred suspension of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.0 g, 43.5 mmol) in methanol (200 mL) was treated with potassium carbonate (35.0 g, 253 mmol) at 25° C. The mixture was then heated at 80° C. for 1 h. At this time, the reaction was cooled to 25° C. The resulting solids were collected by filtration through a sintered glass funnel and then washed with methanol (2×50 mL). The filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (500 mL) and was washed with water (2×200 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solids were triturated with hexanes and diethyl ether to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (10.5 g, 73.4%). 1H NMR (DMSO-d6) δ ppm 8.24 (d, J=8.7 Hz, 1H), 7.28-7.78 (m, 6H), 6.69 (d, J=1.7 Hz, 1H), 3.49 (s, 3H), 1.97 (s, 3H); MS m/e calcd for C18H14ClNO3 [(M+H)+] 328.0. Found 327.9.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:33][CH3:34])[CH2:20][CH2:21][N:22]([CH3:32])[C:23]([C:25]1[NH:26][C:27]([CH:30]=O)=[CH:28][CH:29]=1)=[O:24])[CH3:18]>>[CH2:33]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][N:22]([CH3:32])[C:23]([C:25]1[NH:26][C:27]([CH:30]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])=[CH:28][CH:29]=1)=[O:24])[CH3:34]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCN(C)C(=O)c1ccc(C=O)[nH]1
Product: CCN(CC)CCN(C)C(=O)c1ccc(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]1
Yield: 63 %

Procedure:
6-Phenyl-1,3-dihydroindol-2-one (209 mg, 1 mmol) was condensed with 5-formyl-1H-pyrrole-2-carboxylic acid (2-diethylaminoethyl)methylamide to give 277 mg (63%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:7]2[CH2:12][CH:9]([CH2:10][CH:11]=1)[C:8]2([CH3:14])[CH3:13].B.[O:16]1CCCC1.N.Cl[O-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH:6]1[CH:11]([OH:16])[CH2:10][CH:9]2[CH2:12][CH:7]1[C:8]2([CH3:14])[CH3:13]
Reactant: C1CCOC1
Reactant: COCOCC1=CCC2CC1C2(C)C
Agent: B
Agent: Cl
Agent: N
Product: COCOCC1C(O)CC2CC1C2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To rac-2-[(methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene (3.00 g, 15.3 mmol) in tetrahydrofuran (25 mL), a borane-tetrahydrofuran complex (0.99 M in tetrahydrofuran, 12 mL) was added gradually dropwise at 0° C., and then the resulting reaction solution was warmed to room temperature and stirred for 1 days. The reaction solution was cooled to 0° C., and 28 mass % aqueous ammonia (2 mL) and about 8 mass % aqueous sodium hypochlorite (28 g) were added gradually dropwise successively. The reaction solution was warmed to room temperature and stirred for 1 day. After completion of the reaction, the reaction solution was mixed with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=10/1→4/1) to give rac-2-[(methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-ol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]2[C:25](Br)=[CH:26][CH2:27][N:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[CH:22]=1.[CH2:39]([OH:42])[C:40]#[CH:41].Cl>[Pd](Cl)Cl.C(NCC)C>[ClH:20].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]2[C:25]([C:41]#[C:40][CH2:39][OH:42])=[CH:26][CH2:27][N:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2Br
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: OCC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 40 ml of 98% diethylamine, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide, 3.5 g (10.5 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol was stirred at room temperature under nitrogen for 7 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, and washed with water. The methylene chloride solution was dried over anhyrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 20 g; eluent 20% ether in methylene chloride) gave a colorless oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methanol and ether to give a tan solid, mp 228°-229° C. dec.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCCCC1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)N3CCCCC3)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(piperidin-1-yl)carbonyl]methyl]piperazine hydrochloride
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].C(=O)=O>ClC(Cl)C.ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:15]=2)[CH:10]=[C:9]1[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:22]=[N:21][C:20]=1[O:31][CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNCC1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(C=O)cc2n1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(CN3CCCCC3)cc2n1C(=O)OC(C)(C)C
Yield: 83 %

Procedure:
79 mg 6-Formyl-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is dissolved in 14 mL dichloroethane. 182 □L piperidine and then 0.7 mL acetic acid are added. 334 mg sodium triacetoxyborohydride is added in several portions over 6 hours. Saturated (sat.) aqueous (aq). NaHCO3-solution is added and the reaction mixture is stirred until the CO2-evolution stopped. The reaction mixture is diluted with dichloromethane, the aq. phase washed with dichloromethane, the combined org. phases dried (MgSO4) and concentrated in vacuo. 76 mg (83%) crude product is obtained, which is directly used in the next step.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3]([O-:5])=[O:4].C1([NH2+]C2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH3:1][CH:2]([C:6]1[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)[O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: CCOC(C)=O
Product: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 99.1 %

Procedure:
Dicyclohexylammonium (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetate (Description 4, 31.13 g, 67 mmol) was suspended in ethyl acetate and washed with aqueous citric acid (25%) and water, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless solid (19.0 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.78 (2H, s), 3.90 (1H, q, J 7.2 Hz), and 1.60 (3H, d, J 7.2 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:7]2[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:3][C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Solvent: CC#N
Product: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(N2CCOCC2)n1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 120.7 %

Procedure:
A mixture of 0.46 g of 4-chloro-2-diisopropylaminomethyleneamino-5-(4-chlorophenylethynyl)-pyrimidine, 40 mL of acetonitrile and 0.41 g of morpholine was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue partitioned between water and dichloromethane. The organic layer was washed once more with water, dried over sodium sulfate and filtered. The filtrate was loaded on a column of silica gel equilibrated in the same solvent. After elution of an unknown impurity, the product eluted as a yellow band. Additional material was obtained by a final elution with 1:1 dichloromethane and ethyl acetate. Like fractions of the two eluants were pooled and evaporated to give 0.63 g of a yellow oil, 5-(4-Chlorophenylethynyl)-2-diisopropylaminomethyleneamino-4-morpholinopyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10](OC)=[CH:11][CH:12]=2)[N:7]1[C:17]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:27])=[O:5])[CH3:2].C(C1C(=O)C([Cl:46])=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:46])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The solution of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester (1.0 g, 1.9 mmol) and DDQ (0.73 g, 3.2 mmol) in toluene (50 mL) was heated to 90° C. for 4 h. Then the mixture was cooled to room temperature and washed with NaOH solution (10%) and water. The organic layer was dried with Na2SO4, concentrated in vacuo to give 0.9 g rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2′-oxo-2′,3′-dihydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester as yellow solid. MS: [M+H]+=513
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:12][CH2:13][CH2:14][OH:15].CO>ClCCl>[OH:15][CH2:14][CH2:13][NH:12][CH2:2][C@@H:3]([OH:11])[CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)C#CC[C@H](O)CCl
Reactant: NCCO
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)C#CC[C@H](O)CNCCO
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of (2S)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol (80 g, 420 mmol) and 2-aminoethanol (110 g, 1.8 mol) was stirred at 80° C. for 18 hours. Silica gel chromatography (Gradient: 1% to 10% methanol in dichloromethane) provided the product as a yellow oil. Yield: 30 g, 140 mmol, 33%. 1H NMR (400 MHz, CD3OD) δ 3.80-3.88 (m, 1H), 3.61-3.72 (m, 2H), 2.84 (dd, J=12.3, 3.3 Hz, 1H), 2.69-2.81 (m, 2H), 2.64 (dd, J=12.0, 8.5 Hz, 1H), 2.45 (dd, half of ABX pattern, J=16.6, 5.5 Hz, 1H), 2.37 (dd, half of ABX pattern, J=16.6, 7.0 Hz, 1H), 0.12 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH3:11])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
To (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (1.07 g, 6.25 mmol) and triethylamine (0.87 mL, 6.2 mmol) in CH2Cl2 (15 mL) at 0° C. was added dropwise a solution of 5-chlorothiophene-2-sulfonylchloride (1.34 g, 6.25 mmol) in CH2Cl2 (15 mL). The reaction mixture was warmed to 25° C. and stirred for 24 h. It was then diluted with EtOAc (100 mL) and washed with aqueous 0.1 N HCl (50 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried using Na2SO4 and concentrated. Flash chromatography (eluent: 3:7 EtOAc-hexane) provided 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide (1.66 g, 75%) as a white solid. Recrystallization (EtOAc-heptane, 1:4) provided white needles (1.39 g, 84% recovery), mp 136-137° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[CH2:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH:24]([CH3:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:8]2[C:7]3[C:12](=[CH:13][C:4]([Cl:3])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)[CH:24]([CH3:28])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C1CC=Nc2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccnc2cc(Cl)ccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Sodium hydride (72 mg, 3 mmol) is added to a solution of 7-chloro-4-quinolone (359 mg, 2 mmol) in DMF. After 1 h at 40° C. N-phenyl(trifluoromethylsulfon)imide (1.0 g, 2.8 mmol) and, 1 h later, 1-tert-butoxycarbonyl-3-methylpiperazine (1.8 g, 8 mmol) is added. The reaction mixture is stirred at 80° C. for 2 days, concentrated, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by reversed phase HPLC with water-MeCN-TFA to give the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:9][C:5]1[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncc(Br)nc1Br
Product: Nc1ncc(Br)nc1-c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 19 a using 2-amino-3,5-dibromopyrazine, and 4-fluorophenylboronic acid (commercially available) as starting materials to give the title compound as a white solid, MS (ISP) 268.1, 270.2 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1.C1C(=NNC2C=CC(/C=C/C3C=CC(NN=C4C=CC(=O)C=C4)=CC=3S([O-])(=O)=O)=C(S([O-])(=O)=O)C=2)C=CC(=O)C=1.[Na+].[Na+].[CH3:58][N:59]([CH3:62])[CH:60]=O>>[CH3:58][N:59]([CH:62]=[N:1][N:2]1[NH:6][CH:5]=[C:4]([C:7]2[N:8]([CH3:15])[C:9]([N+:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[S:3]1)[CH3:60]
Reactant: CN(C)C=O
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)S1
Agent: O=C1C=CC(=NNc2ccc(/C=C/c3ccc(NN=C4C=CC(=O)C=C4)cc3S(=O)(=O)[O-])c(S(=O)(=O)[O-])c2)C=C1
Agent: [Na+]
Product: CN(C)C=NN1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
Phosgene gas is bubbled into 100 ml. of N,N-dimethylformamide at 5°-10° C. until 2.0 g. (0.02 mole) is absorbed and a crystalline suspension is formed. This suspension is added in portions to a stirred mixture of 4.5 g. (0.02 mole) of 2-(2-amino-5-thiadiazolyl)-1-methyl-5-nitroimidazole and 100 ml. of N,N-dimethylformamide at 25° C. After 30 minutes the reaction mixture is diluted with 200 ml. of diethyl ether, and the pale yellow solid is collected, washed with ether, and dried. Treatment of this material with 150 ml. of water and drying affords 5.0 g. (89%) of brilliant yellow solid melting at 230°-232° C.