Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[N:18][CH:17]=1
Reactant: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 6-(2-quinolylmethoxy)-3-pyridylmethanol (2.66 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (2.50 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 118–119° C.
Reaction SMILES: [F:1][C:2]([F:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:14]2([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[CH2:16][O:15]2)([F:13])[F:12])=[N:9][CH:10]=1.[NH:32]1[CH:36]=[N:35][N:34]=[N:33]1.C([O-])([O-])=O.[K+].[K+].N#N.[NH4+].[Cl-]>CS(C)=O.C(Cl)Cl>[F:31][C:2]([F:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:13])([F:12])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])([OH:15])[CH2:16][N:32]2[CH:36]=[N:35][N:34]=[N:33]2)=[N:9][CH:10]=1
Reactant: Fc1ccc(C2(C(F)(F)c3ccc(OCC(F)(F)c4ccccc4)cn3)CO2)c(F)c1
Reactant: c1nnn[nH]1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCC(F)(F)c2ccccc2)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 5-(2,2-difluoro-2-phenylethoxy)-2-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridine (81 mg, 0.184 mmol, compound X), and 1H-tetrazole (19.37 mg, 0.277 mmol) in dry DMSO (1229 μl) was added K2CO3 (28.0 mg, 0.203 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. overnight. The reaction was cooled to rt, diluted with CH2Cl2 and poured into a separatory funnel containing sat. aq. NH4Cl. The organic layer was washed and then the aqueous layer was back extracted twice with CH2Cl2. The combined organic layers were then washed three times with water and dried by passing through a phase separator. Volatiles were removed by rotary evaporation and the resulting residue was loaded onto a pad of SiO2 and purified (ISCO, 12 g SiO2, 20-60% ethyl acetate to hexanes over 7 min followed by 7 min at 60%) to afford the title compound 119. Yield=56 mg (59.6%) of a light yellow viscous oil. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.21 (d, J=2.8 Hz, 1H), 7.57-7.45 (m, 6H), 7.41 (s, 1H), 7.33-7.24 (m, 2H), 6.80-6.70 (m, 1H), 6.70-6.62 (m, 1H), 5.58 (d, J=14.3 Hz, 1H), 5.07 (d, J=15.1 Hz, 1H), 4.42 (t, J=11.9 Hz, 2H). 1H decoupled-19F NMR (376 MHz, CDCl3) δ −102.97 (dd, J=261.4, 15.2 Hz, 1F), −103.88 (ddd, J=43.5, 14.9, 9.8 Hz, 1F), −104.07 (s, 2F), −108.15 (d, J=9.7 Hz, 1F), −110.87 (dd, J=261.4, 43.2 Hz, 1F). MS(ESI): m/z calcd for C23H17F6N5O2: 509.404; found: 510.2 (M+H)+, 508.6 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.C([BH3-])#N.[Na+].Cl.[CH3:32][C:33]([CH3:35])=O>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:33]([CH3:35])[CH3:32])[CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)N1CCC(OC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 67 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide (100 mg, 0.205 mmol), acetone (0.075 mL), and sodium cyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl, 63 mg (67%) of the title compound as a hydrochloride salt.
Reaction SMILES: NC1C=CC(OC)=C2C=1C(=O)N(C)C2.[CH2:15]([O:17][C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]2[C:19]=1[CH2:20][N:21]([CH3:31])[C:22]2=[O:30])[CH3:16]>>[NH2:27][C:24]1[CH:25]=[CH:26][C:18]([O:17][CH2:15][CH3:16])=[C:19]2[C:23]=1[C:22](=[O:30])[N:21]([CH3:31])[CH2:20]2
Reactant: CCOc1ccc([N+](=O)[O-])c2c1CN(C)C2=O
Agent: COc1ccc(N)c2c1CN(C)C2=O
Product: CCOc1ccc(N)c2c1CN(C)C2=O

Procedure:
The title compound was prepare according to the procedure for 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A) using 4-Ethoxy-2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (Compound 206B). MS (ES+): m/z 207.16 (100) [MH+]; HPLC: tR=0.78 min (UPLC, analytical).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[I:11]I.CCO>C(O)C>[I:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: II
Solvent: CCO
Product: Ic1ccc(-c2cccs2)s1
Yield: 186.1 %

Procedure:
33.2 g of 2,2'-bithiophene was dissolved in 50 ml of ethanol and I2 /EtOH (20.3 g/220 ml) was added. Then HIO3 /H2O (12 g/20 ml) were added slowly during 2 hours with stirring. The mixture was stirred for further 3 hours and the ethanol was evaporated. The residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. After the solvent was removed, the crude product was vacuum distilled to give 5-iodo-2,2'-bithiophene 36.8 g (105°-110° C./0.1 mm-Hg). The yield is 65-70%. The residue was purified by silica column chromatography and yielded 5.36 g of 5,5'-diiodo-2,2'-bithiophene (6.4%) with melting point of 170° C.
Reaction SMILES: [CH2:1]([C:5]1(O)[C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=2[O:7][C:6]1([CH3:25])[CH3:24])[CH2:2][CH2:3][CH3:4]>C(OCC)(=O)C.CCCCCC>[CH2:1]([CH:5]1[C:9]2[CH:10]=[C:11]([NH:16][C:17](=[O:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=2[O:7][C:6]1([CH3:24])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(O)c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 77 %

Procedure:
Using N-(3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 251, the title compound was synthesized in the same manner as in Example 271. Yield: 77%. Melting point: 129-130° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[O-])[CH3:2].[Li+].Cl.[C:23]1([CH3:31])[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>>[CH3:31][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:30]2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=O)/C=C(\[O-])c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(C)cc2)n1
Yield: 67 %

Procedure:
Starting from 631.5 mg (2.15 mmol) of lithium (1Z)-4-ethoxy-3,4-dioxo-1-[3-(trifluoromethyl)phenyl]but-1-en-1-olate from example 1A and 463.2 mg (2.92 mmol) of 4-tolylhydrazine hydrochloride, 535.8 mg (1.4 mmol, 67% yield of theory) of product are obtained according the method described in example 4A.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:38]4[C:43]([CH:44]=O)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:46]1[CH2:50][C:49](=[O:51])[NH:48][C:47]1=[O:52]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:38]4[C:43]([CH:44]=[C:50]5[S:46][C:47](=[O:52])[NH:48][C:49]5=[O:51])=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccccc2C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccccc2C=C2SC(=O)NC2=O)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
A solution of toluene (10 mL), piperidine (0.04 mL), acetic acid (0.04 mL), 6-[3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)phenyl]-benzaldehyde (0.473 g, 1.06 mmol) and 2,4-thiazolidinedione (0.125 mg, 1.06 mmol) was heated at reflux for 23 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in 30 mL of EtOH. After 20 minutes, the solid was filtered and dried under high vacuum to afford 0.400 g (70%) of 6-[3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)phenyl]-benzylidene-2,4-thiazolidinedione, mp 277–278° C. 1H NMR (300 MHz, DMSO-d6): δ 0.33 (s, 6H), 1.00 (s, 9H), 1.72 (brs, 6H), 2.01–2.09 (m, 9H), 6.89 (d, J=7.8 Hz, 1H), 7.42–7.44 (m, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 12.60 (brs, 1H); 13C NMR (75 MHz, DMSO-d6): ppm −3.6, 18.6, 26.1, 28.4, 36.5, 119.2, 122.5, 125.0, 125.4, 126.6, 130.5, 130.9, 131.0, 131.3, 139.0, 142.0, 154.4, 167.2, 167.6.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]2)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:23][CH:18]1[NH:19][CH:20]([CH3:22])[CH2:21][N:16]([CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[CH2:17]1
Reactant: CC1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC(C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(CC2CCN(C)CC2)CC(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of tert-butyl-4-(3,5-dimethylpiperazine-1-carbonyl)piperidine-1-carboxylate (1.9 g, 5.8 mmol) in THF (50 ml) was added LiAlH4 (18.7 mmol) in portions. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with ethyl acetate and methanol then made alkaline with 10% NaOH solution and extracted with ethyl acetate (3×40). The combined organic solution was dried and concentrated to give 1.2 g of desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]([N:20]([CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)C(=O)OC(C)(C)C)[CH2:18][OH:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1.[CH3:47][S:48](Cl)(=[O:50])=[O:49].[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[OH:19][CH2:18][C@@H:17]([NH:20][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16][C:15]1[CH:39]=[CH:40][C:12]([NH:11][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:48]([CH3:47])(=[O:50])=[O:49])=[O:10])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2N)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1NC(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl N-[(1S)-1-[4-[[[(2-aminophenyl)amino]carbonyl]amino]benzyl]-2-hydroxyethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (20.0 mg) in 1,2-dichloroethane (200 μl) were added successively 1.0 M solution of pyridine in 1,2-dichloroethane (54.5 μl) and 1.0 M solution of methanesulfonyl chloride in 1,2-dichloroethane (43.6 μl) at room temperature. After stirring for 2 hours, the solvent was removed by evaporation and the residue was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give a light brown solid. The solid was dissolved in 1,2-dichloroethane (200 μl). To the solution was added trifluoroacetic acid (200 μl) and the mixture was stirred for 30 minutes. The solvent was removed by evaporation to give N-[2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]phenyl]methanesulfonamide trifluoroacetate (20.3 mg) as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11](=O)[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:21])[C:6]=2[CH:5]=[C:4]([CH3:22])[C:3]=1[CH3:23].[OH-].[K+].NN>C(O)CO>[OH:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:21])[C:6]=2[CH:5]=[C:4]([CH3:22])[C:3]=1[CH3:23]
Reactant: COc1ccc(C(=O)c2oc3c(O)c(C)c(C)cc3c2C)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: COc1ccc(Cc2oc3c(O)c(C)c(C)cc3c2C)cc1
Temperature: 150 °C

Procedure:
The crude material from Step 3 was dissolved in ethylene glycol (600 mL) and KOH pellets (125 g) and anhydrous hydrazine (36 mL) were added. The reaction was heated to 150° C. for 2 hr, then cooled to RT (room temperature) and diluted with 10% NH4OAc buffer (1.5 L) and the product was extracted into EtOAc. The crude product was chromatographed on silica gel (5% EtOAc/toluene) to yield the title compound, which was recrystallized in ether/hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCCC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(CCC#N)c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 1-(tert-butyloxycarbonyl)piperazine (1.73 g, 9.3 mmol), 4-bromo-4-phenylbutyronitrile (2.5 g, 11 mmol) and K2CO3 (1.4 g, 10.2 mmol) in DMF (40 mL) was heated at 60° C. for 4 h. After this time the mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (2:1). The piperazine (2.69 g, 88%) was isolated as a pale yellow oil, which solidified on standing in the fridge. 1H NMR (250 MHz, CDCl3) δ1.41 (9H, s), 1.94-2.46 (8H, m), 3.32-3.60 (5H, m), 7.15-7.42 (5H, m). MS (ES+) (330, M+1).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH:42]([CH3:44])[CH3:43])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Yield: 3.4 %

Procedure:
5-Benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (10-03) (650 mg, 47%) was synthesized as a yellow liquid from 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (9-03) (1.7 g, 38.16 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cccc(C(=O)Nc2nnn[nH]2)c1N
Product: Cc1cccc2c(=O)n(-c3nnn[nH]3)cnc12

Procedure:
Reaction of 2-amino-3-methyl-N-(1H-tetrazol-5-yl)benzamide with triethoxymethane gave 8-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 268° C. (dec) after recrystallization from dimethylformamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]3)[C:8]2=[N:11][S:12]([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH:31]([Mg]Br)=[CH2:32]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]3)[C:8]2([NH:11][S:12]([CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])(=[O:14])=[O:13])[CH:31]=[CH2:32])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=NS(=O)(=O)CC[Si](C)(C)C)C1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of tert-butyl 6′-bromo-1′-(((2-(trimethylsilyl)ethyl)sulfonyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (0.4031 g, 0.78 mmol) in THF (3 mL) was added vinylmagnesium bromide (1.0 M in THF, 3 mL, 3.0 mmol) at 0° C. under nitrogen. The mixture was allowed to slowly warm to room temperature over 18 h. The reaction mixture was then quenched with saturated NH4Cl, extracted with EtOAc, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=2.31 min in 3 min chromatography, m/z 543, 545 (MH+), 487, 489 (MH+-56).
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].N1C=CC=CC=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([F:4])([F:3])[F:1])[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C#N)=C(c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of trifluoromethylphenylketone [C.A.S. 434-45-7] (5 g, 28.71 mmol) and ethyl cyanoacetate [C.A.S. 105-56-6] (3.61 mL, 31.58 mmol) in DCM (100 mL) was flushed with nitrogen, then cooled to 0° C. and maintained under a nitrogen atmosphere. Neat titanium(IV) chloride (6.79 mL, 60.30 mmol) was added dropwise, the reaction mixture was stirred for 10 min at 0° C. and then pyridine (1.5 mL) was added dropwise. When the addition was complete, the ice bath was removed, the reaction was stirred for 30 min at r.t., additional pyridine was added (5 mL) and the reaction mixture was stirred for a further 20 h at r.t. The mixture was then diluted in DCM (100 mL) and washed with HCl 2N (2×200 mL), water (300 mL) and brine (100 mL). The organic phase was evaporated to yield intermediate compound D42 (4.8 g, 61%) as a mixture of E/Z isomers, as a colourless oil which was used without further purification.
Reaction SMILES: I[CH2:2][CH:3]1[O:22][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4]1)=[CH:12][CH:11]=[CH:10][N:9]=3.N1CCCCC1>>[CH2:2]=[C:3]1[O:22][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4]1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)OC(CI)C2
Solvent: C1CCNCC1
Product: C=C1Cc2c(n(-c3ccccc3)c3ncccc3c2=O)O1

Procedure:
A solution of 2 g. of 3,9-dihydro-2-(iodomethyl)-9-phenyl-furo(2,3-b)-1,8-naphthyridin-4(2H)-one in 4 g. of dry piperidine is stirred at room temperature for 72 hours. The reaction mixture is diluted with 80 ml. of water, filtered and the solids washed well with water. The aqueous filtrate is made strongly basic with sodium hydroxide solution and filtered. The combined solids are purified on a grade 62 silica gel column using 5 pts MeOH, 95 pts ethyl acetate as solvent. Fraction III is triturated with 2×50 ml. of hot isopropyl ether yielding the title compound, m.p. 259°-261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:32].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1>O1CCCC1.C(OCC)(=O)C>[C:37]([C:34]1([NH:33][C:31]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[N:8]([CH2:11][CH3:12])[C:7]([C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:17]([F:18])([F:20])[F:19])=[O:14])=[CH:6]3)=[O:32])[CH2:35][CH2:36]1)(=[S:48])[NH2:38]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C(N)=S)CC3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.200 g, 0.35 mmol) is initially charged in tetrahydrofuran (5.5 ml) under argon, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (0.305 g, 0.75 mmol) is added and the mixture is stirred at room temperature for 48 h. Then 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (0.150 g, 0.38 mmol) is added again and the mixture is stirred at room temperature for a further 12 h. The reaction mixture is then diluted with ethyl acetate and washed with a sodium hydrogencarbonate solution. The organic phase is dried with magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.025 g (11% of theory) of N5-(1-carbamothioylcyclopropyl)-6-chloro-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.