Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC(C2C3C=C(C4C(C)=CN=C(NCCCC5CCCNC5)N=4)SC=3C=CC=2)=O)CC1.[CH:33]1([NH:36][C:37]([C:39]2[C:47]3[CH:46]=[C:45]([C:48]4[C:53]([Cl:54])=[CH:52][N:51]=[C:50](Cl)[N:49]=4)[S:44][C:43]=3[CH:42]=[CH:41][CH:40]=2)=[O:38])[CH2:35][CH2:34]1.C(OC([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][CH2:70][CH2:71][NH2:72])[CH:65]([CH:73]([CH3:75])[CH3:74])[CH2:64]1)=O)(C)(C)C>>[CH:33]1([NH:36][C:37]([C:39]2[C:47]3[CH:46]=[C:45]([C:48]4[C:53]([Cl:54])=[CH:52][N:51]=[C:50]([NH:72][CH2:71][CH2:70][CH2:69][N:66]5[CH2:67][CH2:68][NH:63][CH2:64][CH:65]5[CH:73]([CH3:75])[CH3:74])[N:49]=4)[S:44][C:43]=3[CH:42]=[CH:41][CH:40]=2)=[O:38])[CH2:35][CH2:34]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC(C)C1CN(C(=O)OC(C)(C)C)CCN1CCCN
Agent: Cc1cnc(NCCCC2CCCNC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Product: CC(C)C1CNCCN1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of racemic 2-[5-methyl-2-(3-piperidin-3-ylpropylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and racemic 4-(3-aminopropyl)-3-isopropylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a solid. ES+(m/z) 513 (35Cl) and 515 (37Cl) [M+H].
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.[Li].Cl[CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]1.[CH2:32]([Si:34]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:35]([F:39])=[C:36](F)[F:37])[CH3:33]>C1COCC1.O>[F:39]/[C:35](/[Si:34]([CH2:40][CH3:41])([CH2:42][CH3:43])[CH2:32][CH3:33])=[C:36](/[F:37])\[CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]1
Reactant: CCCC1CCC(Cl)CC1
Reactant: CC[Si](CC)(CC)C(F)=C(F)F
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(/C(F)=C(\F)[Si](CC)(CC)CC)CC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
74.1 g (0.28 mol) of 4,4′-di-tert-butylbiphenyl are initially introduced in 1000 ml of THF in an argon atmosphere, and 1.6 g (0.23 mol) of lithium (granules) are added at 0° C. After 5 h, the blue solution is cooled to −78° C., and 40.6 g (0.25 mol) of 1-chloro-4-propylcyclohexane are added. After 30 min at this temperature, 49.6 g (0.25 mol) of triethyltrifluorovinylsilane are metered in. The mixture is warmed slowly and stirred at room temperature for 16 h. Water is added, and the batch is extracted with MTBE. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and saturated sodium chloride solution. The solution is dried using sodium sulfate and concentrated under reduced pressure. The residue is digested with methanol, and insoluble material is filtered off. The filtrate is concentrated under reduced pressure, and the residue is purified by column chromatography (SiO2, pentane), giving [(Z)-1,2-difluoro-2-(4-propylcyclohexyl)vinyl]triethylsilane as a colourless oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])O[CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([O:54][Si:55]([CH2:60][CH3:61])([CH2:58][CH3:59])[CH2:56][CH3:57])([CH2:50][CH2:51][CH:52]=C)[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[CH2:5][C:4]1=[O:74])[CH3:2].C[N+]1([O-])CC[O:79]CC1.CC(C)=O.[OH2:87]>C1COCC1.OS([O-])(=O)=O.[Na+].O=[Os](=O)(=O)=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:87][CH:8]([C:42]([CH3:64])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([O:54][Si:55]([CH2:58][CH3:59])([CH2:56][CH3:57])[CH2:60][CH3:61])([CH2:50][CH2:51][CH:52]=[O:79])[CH:46]([O:62][CH3:63])[CH2:45]2)[CH:7]([CH3:65])[CH:6]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[CH2:5][C:4]1=[O:74])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCCC1(O[Si](CC)(CC)CC)CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(CCC=O)(O[Si](CC)(CC)CC)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-triethylsilyloxy-4"-[but-3-en-1-yl]-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyl-dimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (1gm, 0.9 mmole) in THF (50 mL) was added OsO4 (0.15 M in THF, 0.6 mL, 0.09 mmole) and N-methylmorpholine-N-oxide (0.21 gm, 1.8 mmole). The reaction mixture was stirred for 6 hr at room temperature while monitoring the reaction progress by TLC (1:4, acetone:hexanes). The reaction mixture was diluted with saturated NaHSO4 and partitioned between diethyl ether, CH2Cl2 and H2O. The aqueous layer was extracted once with diethyl ether and the combined organic fractions were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude diol product was dissolved in CH3OH (15 mL) and to it was added a solution NaIO4 (0.255 gm, 1.2 mmole) in H2O (5 mL). The reaction mixture was stirred at room temperature for 4 hours and the reaction progress was monitored by TLC (20% acetone:hexanes). The reaction was then partitioned between diethyl ether and H2O. Washed aqueous layer twice with ether and combined. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography (20% acetone:hexanes) to give the title compound (0.6 gm) MASS:(FAB) 1075 (M+ + Li).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1.[CH2:24]([Br:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[Br-:31].[CH2:24]([N+:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C:2](=[O:1])[CH:3]2[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CS(=O)(=O)Nc1ccc(CCCC2C(=O)C3CCN2CC3)cc1
Reactant: CCCCCCCBr
Product: CCCCCCC[N+]12CCC(CC1)C(=O)C2CCCc1ccc(NS(C)(=O)=O)cc1
Product: [Br-]

Procedure:
In a manner similar to Example II, Method A, react N-[4-(3-(3-oxo-1-azabicyclo[2.2.2]oct-2-yl)propyl)phenyl]-methanesulfonamide with heptyl bromide to yield the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@@H:8]([NH:16][C:17]([C:19]1[N:20]=[C:21]([C:37]#[N:38])[C:22]2[C:27]([C:28]=1[OH:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:23]=2)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:37]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)[C:28]([OH:29])=[C:19]([C:17]([NH:16][C@@H:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][C:6]([OH:39])=[O:5])=[O:18])[N:20]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1nc(C(=O)N[C@H](CC(=O)O)Cc2ccccc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
(S)-3-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-4-phenyl-butyric acid tert-butyl ester (50 mg, 0.096 mmol) was dissolved in CH2Cl2 (4 mL) and cooled in an ice bath. Trifluoroacetic acid (4 mL) was added, and the mixture was stirred at r.t. for 2 h. The solvent was evaporated in vacuo, and the residue was partitioned between saturated NaHCO3 and EtOAc. Hydrochloric acid (1 M) was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was first purified by column chromatography (0-40% EtOAc/hexanes+2% AcOH), then by preparative TLC (60% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound as a pale brown solid. MS: (+) m/z 468.14 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[S:8])[NH:6][NH2:7].[CH3:12][CH:13]([C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>C(O)C.C(Cl)Cl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[S:8][C:24]([CH:13]([CH3:12])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:7][N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=S)c1cccc(F)c1
Reactant: CC(CCNC(=O)OC(C)(C)C)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC(CCNC(=O)OC(C)(C)C)C1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
To a solution of 3-fluorobenzothiohydrazide (300 mg, 1.76 mmol) in ethanol/DCM (6 mL/2 mL) was added tert-butyl 3-methyl-4-oxo-4-phenylbutylcarbamate (538 mg, 1.94 mmol). After stirring at room temperature for 16 hours, acetic acid (3 drops) was added and the mixture stirred for another 48 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to provide the product (366 mg, 48%) as a mixture of diastereomers as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[N:19]1([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(=O)C>C(O)CCC>[CH:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)[N:7]=2)[C:9]1=[O:18])([CH3:17])[CH3:16]
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C)C1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 35.2 %

Procedure:
A solution of 1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step C, 4-(morpholin-4-yl)aniline (77 mg) and acetic acid (25 jL) in 1-butanol (2 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (54 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH2:31][CH2:32]CS([O-])(=O)=O)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:32][CH2:31][CH2:30][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CS(=O)(=O)Oc1ccccc1CCCCCS(=O)(=O)[O-]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Product: CCOC(=O)C(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)OCC

Procedure:
2-Ethoxy-3-{4-(4-(2-methanesulfonyloxyphenyl)butoxy]phenyl}propanoic acid ethyl ester was synthesized using the same method as in Example 1b from 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) and 4-(2-methanesulfonyloxyphenyl)butylmethanesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[NH:34][C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][C:30]=3[N:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(C3CN(C(=O)OC(C)(C)C)C3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To the mixture of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.94 g, 24.6 mmol) in DMF (30 mL) and pyridine (30 mL) was added CDI (4.38 g, 27 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 4-methyl-benzene-1,2-diamine (3 g, 24.6 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (30 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound (4.6 g, yield 61%) as yellow solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1.O>[O:17]1[CH:18]=[CH:19][C:15]2[CH:14]=[C:13]([B:22]([OH:25])[OH:23])[CH:21]=[CH:20][C:16]1=2
Reactant: COB(OC)OC
Reactant: Brc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of n-butyl lithium in hexane (1.5M; 3.72 ml, 5.6 mmol) was added dropwise to a solution of 5-bromobenzo[b]furan (1.0 g, 5.0 mmol) in tetrahydrofuran (10 ml) under argon atmosphere at −60° C. and the mixture was stirred at the same temperature for 30 min. To the mixture was added trimethyl borate (0.69 ml, 6.0 mmol) and temperature of the mixture was raised to room temperature in 4 hrs. Water (5 ml) was added to the reaction mixture at 5° C. and tetrahydrofuran was distilled off under reduced pressure. To the residue was added 1N hydrochloric acid (pH 1) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried. The solvent was distilled off and the residue was triturated with a mixture of n-hexane/diethyl ether, filtered and dried to give 5-benzo[b]furan boronic acid (551 mg) as a pale brown solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(O[C:26](C)([CH3:28])[CH3:27])=O.BrC(C)C.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH:26]([CH3:28])[CH3:27])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)Br
Product: CC(C)Oc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 62 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 2-bromopropane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 62 as a colorless oil (22 mg, 52% over 2 steps) after purification by HPLC.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>ClCCl>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Product: CN(C(=O)Oc1cccc(Oc2ccc(C(F)(F)F)cn2)c1)c1ccccc1

Procedure:
The title compound was prepared from 3-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to flash chromatography (Quad flash 25, dichlormethane) (89%, oil). HPLC-MS m/z=389.1 (M+1), Rt: 5.08 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[NH2:25][C:26]1[CH:31]=[C:30]([C:19]2[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=[C:15]([CH:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: Nc1cccc(B(O)O)c1
Product: CCOc1cc(-c2cccc(N)c2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 155, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoro-methanesulphonyloxy-phenyl)-acetate by reaction with 3-aminophenylboronic acid there was obtained the compound methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-cyano-phenylamino)-acetate, which was converted into methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride; MS: 419 ([M+H]+).
Reaction SMILES: [H][H].C1OC1.[CH2:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C1OC1.C(C1(O)CCCCC1)CCCCCCCC>[CH2:6]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCc1ccccc1O
Reactant: [H][H]
Agent: CCCCCCCCCC1(O)CCCCC1
Solvent: C1CO1
Product: CCCCCCCCCC1CCCCC1

Procedure:
The consumed amount of hydrogen during the reaction was 136.6 mmoles and was 3.01 moles per 1 mole of charged nonylphenol ethylene oxide adduct. Nonylphenol ethylene oxide adduct residual in nonylcyclohexanol ethylene oxide adduct was determined by liquid chromatography. The amount was 120 ppm by weight. Further, nonylcyclohexane formed by hydrogenation decomposition reaction was determined by gas chromatography. The amount was 150 ppm by weight.
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:27][CH3:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=2)[C:10]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:9]1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:36].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:27][CH3:28])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:36])[CH:13]=[CH:14][CH:15]=2)[C:10]([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[N:9]1)[CH3:3]
Reactant: O=C=O
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CC(C)Br
Solvent: CCOCC
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(O)c12
Reaction time: 12 h
Yield: 39 %

Procedure:
To 20 ml of diethyl ether containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 3.92 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-chloroindazole, 2.0 g of isopropyl bromide and 20 ml of diethyl ether. Into the mixed solution were introduced dried oxygen gas and dried carbon dioxide gas for 12 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.46 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-hydroxyindazole having the following analytical values in a yield of 39%.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[CH3:11][CH:2]([S:12][C:13]#[N:14])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(SC#N)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 2-bromopropiophenone (7.14 ml, 46.9 mmol) and potassium thiocyanate (4.56 g, 46.9 mmol) in ethanol (80 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7.27 g (81.0%) of the desired product as an oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[C:7]3=[CH:11][S:12][C:13]([N:14]4C(=O)C5C(=CC=CC=5)C4=O)=[C:6]3[C:5](=[O:25])[C:4]=2[CH:3]=1.O.NN.[CH2:29](O)C>>[NH2:14][C:13]1[S:12][CH:11]=[C:7]2[C:8]3[C:9]([CH3:29])=[CH:10][CH:2]=[CH:3][C:4]=3[C:5](=[O:25])[C:6]=12
Reactant: CCO
Reactant: O=C1c2cc(Cl)ccc2-c2csc(N3C(=O)c4ccccc4C3=O)c21
Agent: NN
Solvent: O
Product: Cc1cccc2c1-c1csc(N)c1C2=O
Temperature: 25 °C

Procedure:
To a suspension of 2-(6-chloro-8-oxo-8H-2-thia-cyclopenta[a]inden-1-yl)-isoindole-1,3-dione (0.45 mmol, Example 10, Part E) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether:ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12]C(Cl)Cl.C(OCC)(=O)C.CCCCCC>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([CH:7]=1)[CH:11]=[O:12]
Reactant: COc1ccc(F)c(C)c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cc(C)c(F)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 4-fluoro-3-methylanisol was dissolved in 80 ml of dichloromethane, and 10 ml of titanium tetrachloride and 7.5 ml of dichloromethyl methyl ether were added to the solution successively at 0° C. The resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice-water, followed by the addition of 300 ml of ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the resulting mixture was evaporated to give a solid. n-Hexane was added to this solid, and the resulting mixture was filtered. The filter cake was washed with n-hexane to give 5.8 g of the title compound as white crystals.