Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][NH:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:26]=1[N:40]1[CH2:52][CH2:51][N:43]2[C:44]3[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=3[CH:50]=[C:42]2[C:41]1=[O:53])(=[O:22])[CH3:21].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.O.C(OCC)(=O)C>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[CH2:52][CH2:51][N:43]3[C:44]4[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=4[CH:50]=[C:42]3[C:41]2=[O:53])=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][NH:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCNC3)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCNC4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 135 °C
Yield: 37 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 126a (210 mg, 0.65 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (330 mg, 0.7 mmol), DME (6 mL) and 1M aqueous sodium carbonate (1.9 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (38 mg, 0.03 mmol) was added. The mixture was heated in microwave to 135° C. for 15 min. After this time, ethyl acetate (10 mL) and water (10 mL) were added. The separated aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-9:1 CH2Cl2:MeOH to afford a 36% yield (140 mg) of 126b.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:23]1([C:28](N)=[NH:29])C=CC=N1.C(N(CC)C(C)C)C.O>CN(C=O)C>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:28]([NH2:29])=[NH:23])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(N)n1cccn1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: CCN(CC)C(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 100 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine, 1H-pyrazol-1-carboxamidine hydrochloride and diethyl isopropylamine are dissolved in DMF, and the reaction mixture is heated to 100° C., then cooled and diluted by addition of water. The aqueous mixture is extracted with EtOAc, and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-guanidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:13]=[CH:14][C:15]2[C:19]([C:20]([O-:22])=[O:21])=[C:18]([CH3:23])[S:17][C:16]=2[CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:23][C:18]1[S:17][C:16]2[CH:24]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:13]=[CH:14][C:15]=2[C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Clc1ccnc2ccsc12
Reactant: Cc1sc2cc(O)ccc2c1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Yield: 27.2 %

Procedure:
This material was prepared by reacting 7-chlorothieno[3,2-b]pyridine (170 mg, 1.0 mmole) with methyl 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylate 11a (267 mg, 1.2 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner similar to that previously described for example 1. Silica gel chromatography (10% MeOH/CHCl2) provided the title compound as a brown viscous oil (93 mg, 27%) of. 1H NMR (DMSO-d6, 300 MHz) δ8.47 (1H, d, J=5.27 Hz), 8.41 (1H, d, J=8.85 Hz), 8.11 (1H, d, J=5.46 Hz), 7.93 (1H, d, J=2.07 Hz), 7.55 (1H, d, J=7.55 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.64 (1H, d, J=5.27 Hz), 2.77 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 18 mg (86%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([Cl:27])[CH:17]=1.[H-].[Na+].S(OC)(O[CH3:35])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:35][O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:28])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[C:18]([Cl:27])[CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(C=Cc1ccc(OC(F)(F)F)c(Cl)c1)c1c(O)c2ccccc2oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1c(C(=O)C=Cc2ccc(OC(F)(F)F)c(Cl)c2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 15 ml of hexamethylphosphoramide was dissolved 1.37 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]1-oxo-2-propenyl]-2H-1-benzopyran-2-one, to this solution was added 0.17 g of sodium hydride (60% oily), and this was stirred at room temperature for 30 minutes. Then, 0.8 ml of dimethyl sulfate, and this was stirred at 65° C. for 2 hours. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with t-butyl methyl ether to obtain 0.38 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (2c-17)] as a pale yellow crystal.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:2]([NH:1][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:3]([NH2:5])=[O:4])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccc([C@@H](N)C(N)=O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N[C@@H](C(N)=O)c2ccc(OC)cc2)cc1
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
A solution of (R)-2-amino-2-(4-methoxyphenyl)acetamide (200 g, 1.11 mol), triethylamine (124 g, 1.22 mol) in dimethylformamide (2 L) is cooled to 5° C. in an ice bath and (4-methoxyphenyl)acetyl chloride (225 g, 187 mL, 1.22 mol) is added dropwise at a rate which maintains the temperature in a range from 5° C. to 7° C. After 1.5 hours the additional stirring in the cold, the reaction solution is transferred to a vessel containing water (12 L). The solid which forms upon standing is collected and rinsed several times with water. The material collected is dried to a constant weight affording 323.9 g (89% yield) of the desired product. Analysis by chiral HPLC indicates 98.6% enantiomeric purity.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:15]2[CH:14]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C(O)C>[CH:12]1[C:13]2[CH:14]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:15]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COC1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
10 ml of 1N sodium hydroxide was added dropwise to a solution of 2.28 g of ethyl 9-fluorenyloxyacetate in 40 ml of ethanol, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and water was added. After washing with ether, the pH value of the aqueous layer was adjusted with 18% hydrochloric acid to 3 to 4 under ice-cooling, followed by extraction with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to give 1.77 g of 9-fluorenyloxyacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:33])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[Cl:32])[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.CO.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:34])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([O:17][CH:18]([F:19])[F:20])[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][C:23]=1[Cl:32])=[C:8]2[CH3:33]
Reactant: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(Cc2ccc(S(C)(=O)=O)cc2Cl)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)O)c12

Procedure:
A solution of [8-chloro-3-(2-chloro-4-methanesulfonylbenzyl)-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.50 g), methanol (10 mL), saturated aqueous lithium hydroxide solution (0.5 mL) and water (1.0 mL) was stirred at 40° C. for 3 hours. The methanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water, methanol and diethyl ether, and then dried to afford title compound as a white solid, 0.15 g.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]([O:6][CH3:7])=[O:5].FC(F)(F)C(O)=O.[CH3:15][N:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:27]([C:40]([F:43])([F:42])[F:41])[CH:26]=3)[N:21]=[C:20]([C:44]#[N:45])[C:19]=2[N:18]=[N:17]1.CCN(C(C)C)C(C)C>CO>[C:44]([C:20]1[C:19]2[N:18]=[N:17][N:16]([CH3:15])[C:24]=2[CH:23]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH:34]3[CH2:35][CH2:36][N:37]([CH2:3][C@H:2]([OH:1])[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:39]3)=[C:27]([C:40]([F:42])([F:43])[F:41])[CH:26]=2)[N:21]=1)#[N:45]
Reactant: COC(=O)[C@@H]1CO1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](O)CN1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1

Procedure:
(S)-Methyl oxirane-2-carboxylate (1.837 mmol, 0.188 g), 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate (0.918 mmol, 0.5 g) and Hunig's base (1.837 mmol, 0.304 ml, 0.237 g) were heated in Methanol (5 ml) to 100° C. for 10 minutes in the microwave. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography, eluting with DCM—90/10 DCM/MeOH to afford (S)-methyl 3-(4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoro-methyl)phenoxy)ethyl)piperidin-1-yl)-2-hydroxypropanoate. (0.34 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:24](=[O:25])[N:23]([CH3:26])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=[S:22])[NH2:21])=[CH:16][CH:15]=3.[Cl:27][CH2:28][C:29]([CH2:31]Cl)=O>>[Cl:27][CH2:28][C:29]1[N:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]2[N:23]([CH3:26])[C:24](=[O:25])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)[S:22][CH:31]=1
Reactant: O=C(CCl)CCl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(N)=S)ccc3[nH]c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CCl)cs4)ccc3[nH]c21

Procedure:
The process is carried out as in Example 75, with compound A: 3-(2,4-dichlorophenyl)-1-methyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indole-6-carbothioic acid amide and 1,3-dichloroacetone.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:11][S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[S:18].CN(C)C=O>O>[CH3:11][S:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[S:18][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:19]=1
Reactant: CSCCCNC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CSCCCNc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (1.99 g), N-[3-(methylthio)propyl]thiourea (1.64 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.85 g, yield 70%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Cl:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Cl:10])=[CH:4][C:3]=1[NH:11][C:12]([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[Cl:14])=[O:13]
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C=Nc1cc(Cl)c(F)c(Cl)c1F
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(Cl)c(F)c(Cl)c1F
Reaction time: 5 h

Procedure:
A mixture of 9.0 gm (0.040 mol) of 2,4-difluoro-3,5-dichlorophenyl isocyanate, 6.5 gm (0.042 mol) of 2-chlorobenzamide, and 100 ml of xylene was boiled for five hours under reflux. It was then allowed to cool, and the product which precipitated was removed by suction filtration and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11](N)=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.CC(C1C=CC=C([NH2:27])C=1)=O>>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:27])[CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: CC(=O)c1cccc(N)c1
Product: NC1=c2ccoc2=NCN1c1cccc(N)c1

Procedure:
The compound was prepared following the procedures described in making 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9), using 3-aminoacetophenone instead of 4-aminoacetophenone as starting material. MS(ES) m/e 227 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][N:34]([CH2:39][CH2:40][OH:41])[CH2:35]4)=[CH:30][CH:29]=3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(CCO)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (200 mg, 0.41 mmol) was dissolved in DMF (4 mL) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (0.15 g, 0.62 mmol) was added followed by triethylamine (0.17 mL, 1.26 mmol) and sodium iodide (0.006 g, 0.004 mmol). The resulting mixture was stirred at 50° C. overnight. The mixture was concentrated, dried using a vacuum pump for 2 hours. The residue was dissolved in 2 mL dichloromethane and TFA (0.30 mL) was added and the resulting solution was stirred overnight, concentrated and purified by preparative HPLC to afford 32 mg (15%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.33 (m, 1 H), 7.81 (s, 1 H), 7.76 (dd, 1H), 7.63-7.61 (m, 1 H), 7.38-7.29 (m, 5 H), 7.19 (dd, 1 H), 7.11-6.98 (m, 3 H), 6.46 (s, 1 H), 5.65 (s, 2 H), 4.24 (s, 2 H), 3.76 (t, 2 H), 3.67 (s, 2 H), 2.93-2.79 (m, 4 H), 2.69 (t, 2 H); LC-MS [M+H]+=530.3, RT=2.36 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][CH3:10].[CH2:29]([S:31][CH2:32][C:33]([OH:35])=O)[CH3:30].Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:17])[F:18])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]([CH3:10])[C:33](=[O:35])[CH2:32][S:31][CH2:29][CH3:30]
Reactant: CCSCC(=O)O
Reactant: CNCc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCSCC(=O)N(C)Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl

Procedure:
To a solution of 0.10 g of 3-[3-chloro-4-[N-(methyl)aminomethyl]phenyl]-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole and 0.038 g of (ethylthio)acetic acid in 3 mL of dichloromethane, 0.089 g of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride was added and the resultant mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was washed with water (5 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and then the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:5 to 1:3) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.083 g of the objective substance as a colorless resinoid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]1[N:24]=[N:25][S:26][C:27]=1[C:28](O)=[O:29].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:28]([C:27]3[S:26][N:25]=[N:24][C:23]=3[CH3:22])=[O:29])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: Cc1nnsc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1nnsc1C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 31.5 %

Procedure:
Preparation of example 16 from the title compound of Example 7 (15 mg, 0.054 mmol), 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (8 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Additional 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid (1.0 mg, 0.006 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.0 mg, 0.006 mmol) were added after c.a. 18 hours to drive the reaction to completion. Silica gel chromatography, also in an analogous manner, followed by diethyl ether trituration afforded the title compound (7 mg, 0.017 mmol) as a yellow powder in 32% yield.
Reaction SMILES: [C:1]1([CH2:11][NH:12][CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[CH:25]=[N:24][CH:23]=2)[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCl>[CH3:48][O:47][C:45]([N:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:13][C@@H:14]([NH:19][C:20](=[O:36])[CH2:21][C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[CH:25]=[N:24][CH:23]=1)[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:46]
Reactant: CC[C@H](C)[C@@H](CNCc1cccc2ccccc12)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Reactant: COC(=O)Cl
Agent: ClCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(Cc1cccc2ccccc12)C(=O)OC)NC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product of Example 2 (40 mg, 0.083 mmol) in CH2 Cl2 (1 ml) and triethylamine (24 μl, 0.17 mmol) at 0° C. was added methyl chloroformate (39 μl of a 2.1M solution in CH2 Cl2, 0.082 mmol). The reaction was stirred at room temperature for 3 hr, the solvent evaporated in vacuo and the residue purified by preparative HPLC (C-18; 95:5 to 5:95 water:CH3CN containing 0.1% trifluoroacetic acid; gradient elution). Lyophilisation of the collected fractions afforded the title compound as a white solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: c1cc2c(o1)CNCC2
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(2-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(OCC)C.[C:24]([Li])([CH3:27])([CH3:26])[CH3:25]>CCCCC>[OH:1][CH:2]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:3][CH2:4][C:5]([CH3:18])=[CH:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]2[CH2:13][CH2:14][O:15][C:11]=2[CH:10]=1
Reactant: CC(=CCOc1ccc2c(c1)OCC2)CCC=O
Reactant: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(=CCOc1ccc2c(c1)OCC2)CCC(O)C(C)(C)C

Procedure:
1.94 g. of 6-[(6-oxo-3-methyl-2-hexenyl)-oxy]-2,3-dihydrobenzofuran are dissolved in 80 ml. of absolute diethyl ether and treated dropwise at 0° C. under nitrogen over a period of 20 minutes with 5 ml. of a 2-M solution of tertbutyl lithium in pentane. The mixture is then poured into ice-cold saturated aqueous ammonium chloride solution and extracted twice with diethyl ether. The extracts are dried over sodium sulfate and evaporated. There is obtained crude 6-[(6-hydroxy-3,7,7-trimethyl-2-octenyl)-oxy]-2,3-dihydrobenzofuran which is used in the process without further purification.