Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:48][N:49]([CH3:54])[CH2:50][CH2:51][NH:52][CH3:53].C(Cl)(Cl)Cl.CC(C)([O-])C.[Na+].C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:52]([CH3:53])[CH2:51][CH2:50][N:49]([CH3:54])[CH3:48])=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Reactant: CNCCN(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N(C)CCN(C)C)nc3)cn2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A toluene solution (60 ml) of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.30 mmol) obtained in Step A, N,N,N′-trimethyl ethylenediamine (60 μl, 46 mmol), Pd2(dba)3.CHCl3 (20 mg, 0.019 mmol), sodium-tert-butoxide (44 mg, 0.45 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (31 mg, 0.092 mmol) was degassed under ultrasonic irradiation, followed by refluxing for 14 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and diluted with water, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, and subsequently magnesium sulfate was filtered off. Subsequently, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1), to obtain a crude product of N-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine as a pale yellow solid (110 mg). Then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound as a yellow powder (40 mg, 54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: Clc1cncc(Cl)n1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccnc3ccccc23)n1
Yield: 14 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 4-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt cyclohexane, 1:1), the title compound was obtained (60 mg). Yield: 14%. 1H NMR (250 MHz, DMSO-d6) δ 7.45 (d, 1H, Harom 3, J=4.9 Hz), 7.67 (t, 1H, Harom 7, J=7.6 Hz), 7.86 (t, 1H, Harom 6, J=7.8 Hz), 8.12 (d, 2H, Harom 3+5, J=8.7 Hz), 8.67 (s, 1H, HPz 5), 8.82 (s, 1H, HPz 3), 8.94 (d, 1H, Harom 2, J=4.9 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[N:19]=[CH:18][CH:17]=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>ClCCl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[N:16]1[N:15]([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[N:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2nccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](Cn2nccn2)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(2H-1,2,3-triazol-2-ylmethyl)cyclopentan-1-amine (500 mg, 1.87 mmol) using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 528 mg of the amine as its TFA salt, which was used as such for the coupling reaction. Step 3: Coupling reaction of Step 2 intermediate (528 mg, 1.87 mmol) with Intermediate 17 (162 mg, 0.94 mmol) in the presence of potassium carbonate (780 g, 5.63 mmol) and NaI (141 mg, 0.94 mmol) in THF (30 ml) as described in Example 1, Step 3 gave 90 mg of the product as a white solid; IR (KBr) 3437, 2955, 2236, 1656, 1420 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.16–1.25 (m, 1H), 1.46–1.62 (m, 2H), 1.70–1.87 (m, 3H), 1.95–2.34 (m, 5H), 2.54–2.65 (m, 1H), 3.09–3.18 (m, 1H), 3.36–3.62 (m, 4H), 4.43 (d, J=7.2 Hz, 2H), 4.76–4.78 (m, 1H), 7.58 (s, 2H).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([NH:43][C:44](=[S:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(OC)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: COc1cccc(NC(=S)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)c1
Yield: 82 %

Procedure:
The compound of example 263 was prepared analogous to compound of example 257 by hydrolysis of compound of example 262.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1.Cl.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[C:4]=2[CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: O=C1c2ccccc2COc2ccc(Br)cc21
Agent: Cl
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 100 °C

Procedure:
Reflux 43 gm. (0.1488 mole of 2-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin and 16 gm. (0.178 mole, 20% excess) of cuprous cyanide in 150 cc. of N,N-dimethylformamide for 24 hours. Cool to 100° C. and pour into a solution of 100 gm. of ferric chloride in 140 cc. of 5% aqueous hydrochloric acid with stirring. Keep the mixture at 70° C. for 30 minutes cool, filter and wash the solids with water. Dissolve the solids in methylene chloride and purify by filtering through a short column of silica gel (m.p. 160°-161° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=[CH:5][C:6]=1[NH:15][NH2:16]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)c(Cl)c1Cl
Yield: 79.4 %

Procedure:
100 g of 2,3,4-trichlorobenzotrifluoride are initially introduced, 200 ml of pyridine are added, followed by 100 g of hydrazine hydrate and the mixture is then heated to the reflux temperature for 12 hours. Thereafter, 90% of the pyridine is distilled off and the remaining residue is stirred into 250 ml of water. The crystalline product is filtered off under suction, washed with a little water and dried. 78 g of 2,3-dichloro-4-trifluoromethyl-phenylhydrazine having a melting point of 79° to 80° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11](O)([C:13](=O)[CH3:14])[CH3:12].C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH3:14][C:13]1[C:11]([CH3:12])([CH3:10])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: CC(=O)C(C)(C)O
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2
Temperature: 220 °C
Reaction time: 3 h

Procedure:
246 parts of p-anisidine, 204 parts of 2-methyl-2-hydroxy-butan-3-one and 10 parts of acetic acid in 650 parts of toluene are heated, with removal of water from the system, until no more water separates off. The solvent is then distilled off and the residue is heated for 5 hours at 220° C. After cooling to 160° C., 10 parts of concentrated sulfuric acid are added; the mixture is kept at 160° C. for 3 hours, whilst distilling off the water formed. Distillation under reduced pressure (21 mbar) gives 318.7 parts of 5-methoxy-2,3,3-trimethyl-indolenine (melting point 53°-54° C.), corresponding to 84.3% of theory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[CH2:9])=[CH:4][CH:3]=1.B.C1C[O:33]CC1.[OH-].[Na+].OO.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH2:9][OH:33])=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(F)cc1)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: OO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(CO)c3ccc(F)cc3)cn2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
Tert-butyl 4-(5-(1-(4-fluorophenyl)vinyl)pyrimidin-2-yl)piperazine-1-carboxylate (1.2 g, 3.12 mmol) was dissolved in THF (30 mL) and then cooled to 0° C., followed by the addition of BH3.THF (6.24 mL, 6.24 mmol) dropwise. The mixture was stirred at RT for 3 h. To the mixture was added H2O in THF (10%, 8 mL), a solution of NaOH (1.25 g) in 30 mL H2O and H2O2 (35%, 18 g) sequentially at 0° C. The mixture was stirred at RT overnight. The mixture was acidified with 1 N HCl and extracted with EA (3×50 mL). The organic phases were washed with aqueous NaHCO3 (50 mL), brine (50 mL), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (DCM:CH3OH=30:1) to get the title compound as a white solid (0.3 g, 24%). MS (ES+) C21H27FN4O3 requires: 402. found: 403 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of phenylmethyl 2-(3-hydroxypropyl)-1-piperidinecarboxylate (2.14 g, 7.72 mmol) in anhydrous dichloromethane (34 ml) was added carbon tetrabromide (5.12 g, 15.43 mmol)). The resulting solution was cooled in ice/water. A solution of triphenylphosphine (4.05 g, 15.43 mmol) in 10 ml dry DCM was added dropwise over 30 mins., producing a deep amber/brown solution. After complete addition the reaction was allowed to warm slowly to ambient temperature and stirring continued overnight. The reaction mixture was filtered to remove the precipitate, washed with ether and the filtrate evaporated to approx 10 ml. This was then loaded onto a 100 g silica cartridge and purified by chromatography using a gradient of Flashmaster 0-25% ethylacetate in cyclohexane over 40 mins. on a Flashmaster collecting all the eluent. The product peak was identified by TLC and the fractions combined and evaporated in vacuo to give the title compound as a clear oil (2.13 g).
Reaction SMILES: [OH:1][NH:2]/[C:3](/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[N:4]\[H].Cl.C(N=C=NCCCN(C)C)C.[O:27]=[C:28]1[C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][N:29]1[CH2:46][C:47](O)=O.CN(C)C=O>ClC(Cl)C>[NH:11]1[C:12]2[C:8](=[CH:7][C:6]([C:3]3[N:4]=[C:47]([CH2:46][N:29]4[CH2:30][CH2:31][CH2:32][C:33]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:27])[O:1][N:2]=3)=[CH:14][CH:13]=2)[CH:9]=[N:10]1
Reactant: [H]/N=C(\NO)c1ccc2[nH]ncc2c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc4[nH]ncc4c3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
(Z)—N-hydroxy-1H-indazole-5-carboximidamide (0.055 g, 0.312 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.120 g, 0.624 mmol) and 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.097 g, 0.312 mmol; Example 68E) were stirred together in dichloroethane (1 mL) at room temperature for 20 minutes. N,N-Dimethylformamide (0.2 mL) was added and stirring was continued for 2 hours and a dark solution resulted. The reaction was heated to 85° C. and stirred overnight. The reaction was cooled, concentrated, loaded onto a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=18 mL/minute) over 30 minutes. The material obtained was subjected to a second chromatography on a GraceResolv™ 4 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 0.5% methanol/dichloromethane to 7.5% methanol/dichloromethane (Flow=18 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.30 (s, 1H), 8.01 (dd, J=1.2, 8.8, 1H), 7.75 (d, J=8.7, 1H), 7.45-7.07 (m, 10H), 4.92 (s, 2H), 3.66 (t, J=6.3, 2H), 2.76-2.57 (m, 2H), 1.78 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)[C:7]([Cl:19])=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C@@H:36]([NH2:38])[CH3:37])=[N:34][CH:35]=1>CCCCO.O>[Cl:19][C:7]1[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[N:9][C:2]([NH:38][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][N:34]=2)[CH3:37])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCCCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(Cl)cc1C#N)c1ccc(F)cn1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of 2,5-dichloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)nicotinonitrile (Method 43, 0.60 g, 2.04 mmol), DIEA (0.34 g, 2.65 mmol), and (5)-1-(5-fluoropyridin-2-yl)ethanamine (Method 33; 0.90 g, 6.12 mmol) in n-BuOH was heated to 120° C. for 9 hours. The reaction was then cooled to room temperature, diluted with water (20 ml), and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.42 g, 52%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=2.7 Hz, 1H), 7.61 (s, 1H), 7.51-7.49 (m, 1H), 7.38-7.32 (m, 1H), 6.06 (br s, 1H), 5.28-5.22 (m, 1H), 1.94-1.88 (m, 1H), 1.58 (d, J=6.9 Hz, 3H), 1.01 (br s, 2H), 0.76-0.75 (m, 2H). MS: Calcd.: 397. Found: [M+H]+ 398.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16](=[O:17])[C:18]2[S:19][C:20]([CH3:29])=[C:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=23)[CH:5]=[C:6]([O:12][CH3:13])[C:7]=1[O:8][CH2:9][CH2:10][O:11][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(Cl)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 3-[3-chloro-4-(2-hydroxyethoxy)-5-methoxy-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (160 mg, 0.40 mmol) in DCM (10 mL) and DIPEA (0.11 mL, 0.64 mmol) is added methane sulfonylchloride (0.04 mL, 0.48 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2-chloro-6-methoxy-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-ethyl ester (183 mg) as a yellow oil; LC-MS: tR=1.15 min, [M+1]+=515.15.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]2[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:4]=2[N:3]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[N:36][NH:37][CH:38]=1)=[O:33])[CH3:30]>[Cl-].[Na+].O>[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[N:36][N:37]([C:2]2[N:6]([CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:4]=3[N:3]=2)[CH:38]=1)=[O:33])[CH3:30]
Reactant: COCCOCn1c(Cl)nc2c(Cl)cccc21
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3n2COCCOC)c1
Temperature: 80 °C

Procedure:
To a mixture of 2,4-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole (0.660 g, 2.40 mmol) and DMF (10 mL), was added Cs2CO3 (1.88 g, 5.76 mmol) and 1H-pyrazole-4-carboxylic acid ethyl ester (0.400 g, 2.88 mmol). The resulting mixture was then heated to 80° C. for 2 h. The mixture was cooled to 23° C., poured into brine (40 mL), and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (40 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-50% EtOAc/hexanes) to yield the titled compound as a mixture of regioisomers (0.880 g, 97%). MS (ESI/CI): mass calcd. for C17H19ClN4O4, 378.1; m/z found, 379.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.97 (s, 1H), 8.80 (s, 1H), 8.22 (s, 1H), 8.20 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.40-7.23 (m, 4H), 6.38 (s, 2H), 6.16 (s, 2H), 4.41-4.31 (m, 4H), 3.68-3.59 (m, 2H), 3.57-3.49 (m, 2H), 3.48-3.41 (m, 2H), 3.41-3.35 (m, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 1.38 (td, J=7.1, 1.2 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH2:24][C:25]([NH:27][C@@H:28]([CH3:31])[CH2:29][OH:30])=[O:26])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH2:24][C:25]([NH:27][C@@H:28]([CH3:31])[CH2:29][OH:30])=[O:26])[CH:23]=2)[N:7]=1
Reactant: C[C@@H](CO)NC(=O)Cn1cc(N)cn1
Reactant: Clc1nccc(NCc2c(Cl)cccc2Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](CO)NC(=O)Cn1cc(Nc2nccc(NCc3c(Cl)cccc3Cl)n2)cn1

Procedure:
A mixture of 2-chloro-N-(2,6-dichlorobenzyl)pyrimidin-4-amine (120 mg, 0.41 mmol), (S)-2-(4-amino-1H-pyrazol-1-yl)-N-(1-hydroxypropan-2-yl)acetamide V-1 (110 mg, 0.54 mmol, prepared by Procedure G1), Xantphos (47 mg, 0.08 mmol), Pd2dba3 (37 mg, 0.04 mmol) and cesium carbonate (333 mg, 1.02 mmol) in dioxane (40 mL) was heated to reflux under nitrogen. Upon completion, the reaction was concentrated in vacuo, diluted with aqueous sodium carbonate solution then extracted with ethyl acetate. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (0-10% v/v [10% NH3 in MeOH]/DCM) to afford (S)-2-(4-((4-((2,6-dichlorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-N-(1-hydroxypropan-2-yl)acetamide I-3 (60 mg, 25%). LC-MS (Method A), RT=8.32 min. (ES+) 450.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([O-:8])=[O:7]>O1CCCC1>[CH:12]([C:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:16]=[CH:15][CH:14]=1)=[CH:4][CH2:3][CH2:2][CH2:1][CH2:15][CH2:16][CH2:9][CH2:10][CH3:11]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
Phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) and triphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500 ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexane solution) over not less than 1 hour at 0° C. After the dropwise addition, the reaction mixture was stirred at said temperature for 30 minutes and at room temperature for 1 hour, and a solution of 3-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwise added thereto at 0° C. over 1 hour. The reaction mixture was stirred at room temperature for 10 hours and filtered. The residue was washed with ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100:1) to give 57.3 g of 3-(1-decenyl)-nitrobenzene (cis/trans=7:3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C(=O)O)cs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of ethyl 2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 1N sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (1.02 g, 96.2%) as crystals.