Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]([O:17][CH2:18][CH:19]=[N:20][OH:21])[CH2:14][CH:15]=[CH2:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl.O>[CH2:4]([O:11][CH2:12][C@@H:13]1[O:17][CH2:18][C:19]2=[N:20][O:21][CH2:16][C@@H:15]2[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
An aqueous solution of sodium hypochlorite (14.5% solution, 600 mL) was added drop-wise to a 0° C. solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (224 g from the previous step, ≦0.759 mol) in dichloromethane (1 L), while the internal temperature was maintained below 15° C. After completion of the addition, the reaction mixture was left to stir at 0° C. for 1.5 hours, then diluted with water (1 L) and dichloromethane (500 mL). The aqueous layer was extracted with dichloromethane (2×500 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), water (500 mL) and again with saturated aqueous sodium chloride solution (500 mL). They were subsequently dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptane) afforded the product as a colorless oil. The indicated relative stereochemistry of compound P1 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. Yield: 85.3 g, 345 mmol, 45% over 2 steps. LCMS m/z 248.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.27-7.40 (m, 5H), 4.77 (d, J=13.5 Hz, 1H), 4.54-4.65 (m, 3H), 4.22 (dd, J=13.5, 1 Hz, 1H), 3.79 (dd, J=11.7, 8.0 Hz, 1H), 3.69-3.76 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.1, 5.9 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.1, 4.3 Hz, 1H), 3.39-3.5 (m, 1H), 2.20 (ddd, J=12.9, 6.5, 1.6 Hz, 1H), 1.51-1.62 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(C#N)cc1
Reaction time: 48 h

Procedure:
A suspension of 4-cyanophenylacetic acid (31.2 g, prepared as described in J. C. S. 744, (1941)), concentrated sulphuric acid (5 ml) and absolute ethanol (300 ml) was boiled under reflux with stirring for 48 hours. The solvent was removed under reduced pressure and dilute aqueous sodium hydroxide solution was added to neutralise the sulphuric acid. Dichloromethane was added. The mixture was filtered and extracted with further dichloromethane. The organic extracts were dried and evaporated to give ethyl 4-cyanophenylacetate, m.p. 94-95° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][CH2:12][CH2:13][C:14]2[NH:15][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][CH2:8]1.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(O)C.CCCCC>[Cl:29][CH2:30][C:31]([N:11]([CH2:10][CH:7]1[CH2:9][CH2:8]1)[CH2:12][CH2:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(-c2c(CCNCC3CC3)[nH]c3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: CCCCC
Product: O=C(CCl)N(CCc1[nH]c2ccccc2c1-c1ccccc1)CC1CC1

Procedure:
3-Phenyl-1H-indol-2-ethanamine are reacted with cyclopropanecarboxylic acid chloride to give N-cyclopropylcarbonyl-3-phenyl-1H-indol-2-ethanamine, which is reduced with lithium aluminium hydride to N-cyclopropylmethyl-3-phenyl-1H-indol-2-ethanamine, which is reacted with chloracetyl chloride to give 2-chloro-N-cyclopropylmethyl-N-[2-(3-phenyl1H-indol-2-yl)ethyl]acetamide, m.p. 104°-106° (from ethanol/pentane).
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:12][N:13]=[CH:14][C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([N:12]1[CH:16]=[C:15]([OH:17])[C:14]([C:1](=[O:2])[CH3:3])=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)C=NNCc1ccccc1
Reactant: O=CC=O
Solvent: O
Solvent: CO
Product: CC(=O)c1nn(Cc2ccccc2)cc1O
Temperature: 25 °C
Yield: 33 %

Procedure:
To a 40% aqueous solution of glyoxal (8.28 g, 6.55 mL, 57.1 mmol) was added a slurry of 2-oxopropanal benzylhydrazone (10.1 g, 57.1 mmol) in water (250 mL) and methanol (25 mL). The resulting mixture was heated at reflux for 3 hours before cooling to room temperature. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (120 g column, 0-100% EtOAc/heptane gradient) to provide 1-(1-benzyl-4-hydroxy-1H-pyrazol-3-yl)ethanone (4.07 g, 33%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])[CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])[CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1cccc(-c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cccc(-c2ccccc2)c1
Yield: 84.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 511 mg of 2-[1-(3-biphenylyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 16), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 916 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([F:26])[C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)=O)(C)(C)C.[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:30]1([S:27]([C:21]([CH:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=4)[NH:8][C:20]=3[CH2:19]2)([F:26])[C:22]([N:23]([CH3:39])[CH3:24])=[O:25])(=[O:28])=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CI
Reactant: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
680 mg (1.27 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 10 mL of DMF were treated with 83 mg (1.90 mmol, 1.5 eq) of NaH (55% in oil) portionwise within 30 min at 0° C. 217 mg (1.52 mmol, 1.2 eq) of methyliodide were added and the reaction was stirred an additional 30 min, and then poured into water and extracted with EtOAc. The crude material was dissolved in 10 mL of CH2Cl2, and 1 mL of TFA was added at RT. Aqueous Na2CO3 was added until pH=7 was reached, and the organic phases were dried on Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1:1 yielded 420 mg (65%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N,N-dimethyl-acetamide as a white solid, MS: 449 (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]=1[NH2:13].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CC(N(C)C)=O>[Cl:14][C:15]1[N:20]=[C:19]([NH:13][C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[CH:11]=[CH:12][C:4]=2[Cl:3])[CH:18]=[CH:17][N:16]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1c(Cl)ccc2c1OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Clc1nccc(Nc2c(Cl)ccc3c2OCO3)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (13.4 g, 60% dispersion in mineral oil) was added portionwise to (5-chloro-1,3-benzodioxol-4-yl)amine (11.5 g, prepared as described in WO2001094341) in DMA (100 ml) at 0° C. 2,4-Dichloropyrimidine (10 g) was added and the reaction warmed to room temperature and stirred overnight. The reaction was quenched cautiously with water, the solution filtered and concentrated and the residue dissolved in DCM, washed with water and brine, dried and concentrated to give 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)pyrimidin-4-amine as a dark brown oil that was used without further purification (16 g, 85%); NMR Spectrum (300 MHz, DMSO) 6.10 (s, 2H), 6.58 (d, 1H), 6.94 (d, 1H), 7.05 (d, 1H), 8.15 (d, 1H), 9.76 (s, 1H); Mass Spectrum M+ 284.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.[Pt]=O>[CH:19]1([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC2CCCC2)cc1OC
Yield: 100 %

Procedure:
500 mg of N-methyl-N-[2-(3 4-dimethoxyphenyl)-ethyl]-1,3-propanediamine and 0.21 ml of cyclopentanone were dissolved in 5 ml of ethanol, followed by the addition of 10 mg of platinum oxide to carry out hydrogenation at a room temperature under 1 atm for 6 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under a reduced pressure to obtain 660 mg of the title compound as a yellow oil (yield: 100%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)Nc2ccc([C@H]3CCC(N4CCC[C@@H]4C)C3)cc2)cc1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)cyclopentyl]-phenylamine (Intermediate 14) and 4-methylbenzoyl chloride.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[O:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:18]([C:14]2[S:13][C:12]([CH2:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:23]1
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC2CCOC2)s1
Yield: 40 %

Procedure:
As described for example 48e, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (75 mg, 0.23 mmol) was converted, using rac-tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (35 mg, 40%) which was obtained as a light brown oil. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[C:3]([Cl:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Cl)c(N)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A mixture of ethyl 7-amino-1H-indole-2-carboxylate (2.30 g), N-chlorosuccinimide (1.40 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.59 g, yield 63%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 217-218° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH2:24]([NH:26][CH3:27])[CH3:25]>>[CH2:24]([N:26]([CH3:27])[C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:22])[F:1])=[N:4]2)=[CH:17][CH:16]=1)[CH3:25]
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCNC
Product: CCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-ethylmethylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-100% ethyl acetate in hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17](I)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:23]([OH:27])[CH2:24][C:25]#[CH:26].Cl>C(NCC)C.CN(C=O)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([C:26]#[C:25][CH2:24][CH2:23][OH:27])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(C#CCCO)cc2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno[2,3-b]pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) is added copper iodide (0.128 g) and Pd(PPh3)2Cl2 (0.032 g) followed by addition of 3-butyn-1-ol (0.20 mL). The reaction is stirred at rt for 18 h. The reaction mixture is partitioned between H2O (100 mL) and ethyl acetate (100 mL). The organic layer is removed, and the aqueous layer is extracted with ethyl acetate (2×100 mL). Combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown oil is purified via column chromatography (CH2Cl2:CH3OH; 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a brown solid. This material is dissolved in DMF (15 mL) and 2N HCl is added until a precipitate forms. The resulting tan solid is purified via column chromatography (CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.183 g (21%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([C:34]1([O:37]C(=O)C)[CH2:36][CH2:35]1)=[O:33]>>[OH:37][C:34]1([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH2:27][CH:28]5[CH2:29][CH2:30]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:33])[CH2:36][CH2:35]1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]2([OH:35])[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)=[C:25]([O:38][CH3:39])[CH:24]=1.C1(O)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]5([OH:35])[CH2:30][C:31]([F:34])([F:33])[CH2:32]5)=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Solvent: CO
Solvent: Oc1ccccc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Temperature: 137.5 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of (E)-methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)thiophene-2-carboxylate (33.9 g, 105 mmol) prepared in Example 1 Part E and 1-((4-amino-2-methoxy-phenoxy)methyl)-3,3-difluorocyclobutanol (27.2 g, 105 mmol) prepared in Part C and phenol (200 g) was heated at 135-140° C. for 45 min while the reaction being monitored by LC. The mixture was diluted with methanol (700 mL), stirred at RT for 15 min and allowed to stand at RT overnight. The precipitated product was isolated by filtration, washed with chilled methanol and dried under vacuum to yield 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (37 g, 73.3 mmol, 69.8% yield) as a white solid. Dilution of the mother liquor with Et2O and hexane precipitated more solid which was triturated with MeOH to yield 1.8 g of a second crop of the desired product. MP 198-199° C. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2 H, d, J=8.56 Hz), 7.08 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=2.27 Hz), 6.95 (1 H, dd, J=8.31, 2.27 Hz), 4.14 (2 H, s), 3.89 (3 H, s), 2.72-2.93 (4 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 157.3, 156.7, 151.8, 150.4, 148.60 (1C, s), 148.0, 135.7, 131.4, 131.4, 129.4, 127.6, 123.1, 120.8, 119.4, 115.7, 117.6 (dd, J=282, 269. Hz), 111.4, 75.5, 64.6 (dd, J=18, 8 Hz), 56.0, 46.0 (t, J=22.89 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:24][CH2:21][C:22]#[CH:23])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCNc1ccc(C(=O)C(F)(F)F)cc1
Yield: 100.1 %

Procedure:
To a solution of 8.64 g (45 mmol) of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (Journal of Organic Chemistry, Vol. 32, pp. 1311-1318 (1967)) and 7.53 ml (54 mmol) of triethylamine in 150 ml of acetonitrile, cooled in an ice-bath, is added 31.13 ml (0.45 mol) of 2-propynylamine. The ice-bath is removed and the solution is heated under reflux for eighteen hours. The reaction solution is cooled and concentrated to give a solid, which is partitioned between ethyl acetate and water. The ethyl acetate layer is separated, dried (magnesium sulfate), and concentrated to give 10.23 g of a red-brown oil. This is applied to a column of 250 g of flash silica gel packed in n-heptane-dichloromethane (2:1). Elution with the same solvent gives 4.05 g (39.6%) of the product as a fluffy white solid; mp 96°-98° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([C:31]6[N:30]=[C:29]([CH3:28])[O:33][N:32]=6)[CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)no1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: Cc1nc(-c2cccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5CCO6)CC4)CC3)c2)no1

Procedure:
The title compound, white solid (125 mg, 97%), MS (ISP) m/z=517.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2nc(Nc3cc[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [6-methoxy-1-(3-methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[NH:13]C(=O)C.O1CCOCC1.[ClH:23]>CO>[ClH:23].[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[NH2:13]
Reactant: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C)c(N)cc1[N+](=O)[O-]

Procedure:
A slurry of N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1 g, 4.46 mmol) in methanol (20 ml) and 4M HCl in dioxane (8.92 ml, 35.7 mmol) was heated at 60° C. for 18 h. The reaction mixture was cooled in an ice bath and solids were filtered and washed with cold methanol to afford 2-methyl-4-(methyloxy)-5-nitroaniline HCl salt (0.516 g, 2.36 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.38 (s, 3 H) 3.91 (s, 3 H) 7.31 (s, 1 H) 7.87 (s, 1 H) 9.39 (br. s., 2 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13](I)[N:14]=[C:7]3[C:6]=2[CH:16]=1.C([Mg]Br)C.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:16]=1
Reactant: Brc1ccc2c(c1)-c1nc(I)cn1CCO2
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc2c(c1)-c1nccn1CCO2
Temperature: 25 °C

Procedure:
To a solution of 10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (9 g, 20 mmol) in THF (40 mL) was added Ethylmagnesium bromide in Ethyl ether (22 mL) at −20° C. The mixture was allowed to warm to room temperature and in one and half hour the completion was showed by LCMS. The reaction mixture was poured into 10% NH4Cl and extracted by EtOAc. Organic layer was washed by brine, dried by MgSO4 and concentrated. The crude was purified by Isco chromatography to afford 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 265 (M+H).