Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[C:22]#[N:23])=[O:16])[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].O.[OH-].[Li+].Cl>C1COCC1.O>[C:22]([C:21]1[CH:20]=[C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[S:18][C:17]=1[C:15]([NH:14][C@@H:4]([CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8])[C:3]([OH:35])=[O:2])=[O:16])#[N:23]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of (S)-2-{[3-Cyano-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (16.2 mg, 0.032 mmol) in THF (1 mL) was added a solution of lithium hydroxide monohydrate (9 mg, 0.009 mmol) in water (1 mL). The mixture was then stirred at room temperature 15 h. The mixture was then acidified with 1N HCl and extracted with EtOAc (×3). The extracts were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. Material was purified by reverse phase HPLC to afford to pure product, 1.7 mg (11%). MS m/e 498.9 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A solution of 2.2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 2.6 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3) in 200 ml of benzene was heated under reflux for about 2 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the reaction mixture was freed from the benzene used as solvent by distillation under reduced pressure, and the resulting residue was dissolved in 150 ml of absolute methanol. 1 g of sodium borohydride was added to this solution, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then mixed with ethyl acetate and with a saturated aqueous solution of sodium chloride. The organic layer was separated and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 40:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the eluent, to give 2.3 g of the title compound having an Rf=0.44 (thin layer chromatography over silica gel, using a 40:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][CH:10]=2)[N:6]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>N1C=CC=CC=1>[C:18]([O:17][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:35](=[O:36])[O:37][CH2:38][CH3:39])[S:3][C:4]=2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:14][CH:13]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCc2nc(N)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (140 mg) was dissolved in pyridine (2 ml) under N2 atmosphere. Then, ethyl chloroformate (30.2 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and concentrated in vacuo. The residue was dissolved in AcOEt, and washed with 1N-HCl, water and brine. The organic layer was dried over anhydrous MgSO4, and concentrated in vacuo to give ethyl {4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}carbamate (155.8 mg) as an off-white amorphous substance.
Reaction SMILES: C(OCC)(=O)C.[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[I-:37].[Na+]>CC(C)=O>[CH2:7]([I:37])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCI

Procedure:
A solution of linoleyl alcohol (5.32 g, 200 mmole) and pyridine (40 ml) was cooled to 0° C. and added to p-toluene-sulfonic chloride (4.2 g, 220 mmole) in 10 ml of pyridine. The resulting solution was stirred overnight at 0° C. and poured into 50 ml of ice water. The organic layer was extracted with 100 ml of ether and the organic layer was washed with 1% aqueous hydrochloric acid until acidic and then washed three times with water. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated to give 6 g of oily material having an Rf of 0.3 on thin layer chromatography (20Δ ethyl acetate/Skelly B linoleyl alcohol Rf =0.1). To the crude tosylate (6 g, 140 mmole) was added acetone (150 ml) and sodium iodide (300 mmole, 4.5 g), and the mixture was heated gently on a steam bath for 3 hours. The solvent was removed in vacuo and 200 ml of ether added thereto. The organic layer was washed twice with an aqueous solution of sodium bisulfite, twice with water and dried over magnesium sulfate, filtered and solvent removed. The crude iodide was purified by column chromatography over silica gel and eluted with Skelly B to yield 5.2 g of linoleyl iodide Rf ethyl acetate--Skelly B (10:90 v/v)=0.7 of formula II of Chart A.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[O:7])[CH2:23]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(C)c([N+](=O)[O-])c3)C2)c1

Procedure:
The compound of Example 30 was prepared according to the general preparation protocol A from 4-methyl-3-nitrobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH:14][NH:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCCC1>[CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:25])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:40][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]=1)=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A mixture of ethyl [2-({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)hydrazino](oxo)acetate (0.43 g), Lawesson's reagent (0.42 g) and tetrahydrofuran (10 mL) was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.29 g, yield 68%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 176-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([C:19]2[C:28]3[C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[S:31][C:27]=3[C:26]([Br:36])=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:16]=[C:15]([Br:37])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]([O:13]C)=[O:12])[C:6]([O:8]C)=[O:7].O>Cl.O1CCOCC1>[Br:1][C:2]1[CH:18]=[C:17]([C:19]2[C:28]3[C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[S:31][C:27]=3[C:26]([Br:36])=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:16]=[C:15]([Br:37])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Reaction time: 14 h
Yield: 46.7 %

Procedure:
A solution of (R)-2-[2,6-Dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d ]thiophen-11-yl)-phenoxy]-succinic acid, dimethly ester (0.317 g, 0.448 mmol) in 4M HCl in dioxane (5 mL) was combined with water (5 mL) and concentrated HCl (1 mL) in a sealed pressure bottle and heated for 9 hours. After remaining at ambient temperature for an additional 14 hours the reaction mixture was partitioned between water and ether. The layers were separated and acid treated silica gel (7 mL) was added to the ether layer. The solvent was removed and the adsorbate was purified by flash chromatography (acid treated silica gel, eluant 80:20 pet. ether:ethyl acetate) to provide the title compound as a white solid (0.142 g, 47%), mp 163-164° C.; [a]D25=+14.16° (8.825 mg/mL, methanol); NMR (DMSO-d6); δ13.6 - 13.2 (broad singlet, 1 H,), 12.7 - 12.6 (broad singlet, 1 H), 8.28 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.82 - 7.78(m, 3 H), 7.65 - 7.57(m, 2 H,), 7.52(dd, J=7, 1 Hz, 1 H), 7.31(dd, J=7, 1, 1H), 6.70(d, J=8 Hz, 1 H), 5.32 (t, J=8 Hz), 3.67(m, 2 H); MS (-FAB) [M-H]-; 3 bromine pattern detected, 675(25%), 677(10%), 679(25%), 681(10%); Anal. Calc. for C26H15Br3O5S: C, 45.78, H, 2.23, N, 0.00. Found: C, 46.42, H, 2.40, N, 0.05.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2].[Li+].CC([N-]C(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]([CH:46]([CH3:48])[CH3:47])([CH2:42][CH2:43][CH2:44]I)[C:40]#[N:41])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].Cl>C1COCC1>[C:1]([C:6]1([CH2:44][CH2:43][CH2:42][C:39]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=2)([CH:46]([CH3:48])[CH3:47])[C:40]#[N:41])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)Cc2cc(OC)c(OC)cc2CN1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The resulting ester of formula 31 is then treated with an iodoalkane of formula 22 (see Scheme III, step 2) in the presence of a strong base to form an alkylated tetrahydroisoquinoline ester of formula 32. For example, 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31) is added to a solution of LDA in THF at -70° C. and allowed to stand for 5-60 minutes, preferably about 10 minutes. To this reaction mixture is then added 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) in THF, and the resulting mixture allowed to warm to about 0° C. The mixture is then acidified, for example with dilute HCl, and the product extracted and purified to produce 3-carboethoxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (32).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:37])[S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=1)[CH2:13][C:14]1[C:19]([O:20][S:33](=[O:35])(=[O:34])[N:32]([CH3:37])[CH3:31])=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(CN(CCCCNC(=O)OC(C)(C)C)Cc2ncccc2OS(=O)(=O)N(C)C)c(C)c1
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a solution of {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-hydroxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.190 g, 0.46 mmol) in CH2Cl2 (4 mL) was added dimethylsulfamoylchloride (0.160 mL, 1.49 mmol), NEt3 (0.300 g, 2.16 mmol) and DMAP (catalytic) and the reaction mixture stirred for 48 h. The mixture was diluted with CH2Cl2 (30 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated. Purification by column chromatography on silica gel with saturated NH4OH in Et2O afforded {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-dimethylsulfamoyloxy-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester (0.054 g, 23%) 1H NMR (CDCl3) δ 1.30-1.53 (m, 13H), 2.11 (s, 3H), 2.25 (s, 3H), 2.50-2.54 (m, 2H), 2.94-3.00 (m, 8H), 3.74 (s, 2H), 3.91 (s, 2H), 5.11 (br s, 1H), 7.16 (s, 1H), 7.23 (dd, 1H, J=6.6, 4.8 Hz), 7.72 (d, 1H, J=8.3 Hz), 8.—(s, 1H), 8.51 (d, 1H, J=4.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.2 %

Procedure:
To a mixture of 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.131 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 4.3 mg (0.0458 mMol) methyl chloroformate. The reaction mixture was mixed for 18 hours at ambient temperature. To this mixture were then added 170 mg (0.137 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 10.2 mg (81%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C([N:8]([C:23]([O:25][CH2:26]C1C=CC=CC=1)=O)[C:9]1[CH:10]=[C:11]([CH:15]=C(C2OC=CN=2)C=1)[C:12]([OH:14])=[O:13])C=C>O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([NH:4][C:9]1[CH:10]=[C:11]([CH:15]=[C:23]([O:25][CH3:26])[N:8]=1)[C:12]([OH:14])=[O:13])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: [Cu+2]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C=CCNc1cc(C(=O)O)cc(OC)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A mixture of 3.97 ml (52 mmol, 10 eq) allylamine, 0.97 g (5.2 mmol, 1 eq) 2-chloro-6-methoxy-isonicotinic acid (see building block A3) and 1.29 g (5.2 mmol, 1 eq)-copper(II) sulfate pentahydrate in 10 ml water is heated in a closed vessel during 2.5 h at a bath temperature of 160° C. After cooling to rt the mixture is diluted with 400 ml aq 10% citric acid and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate and the solvents are evaporated at reduced pressure. The residue is dissolved in about 20 ml hot DCM/MeOH (2/1). On addition of about 25 ml of hexane, partial evaporation of the solvents to a volume of about 20 ml and keeping at 4° C. for 4 h the product precipitates and is filtered off and dried in vacuum.
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([Cl:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][N:61]5[C@H:66]([CH3:67])[CH2:65][NH:64][CH2:63][C@@H:62]5[CH3:68])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1>>[ClH:24].[ClH:56].[ClH:1].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([Cl:56])=[CH:54][N:53]=[C:52]([NH:57][CH2:58][CH2:59][CH2:60][N:61]5[CH:62]([CH3:68])[CH2:63][N:64]([CH3:3])[CH2:65][CH:66]5[CH3:67])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1
Reactant: C[C@@H]1CNC[C@H](C)N1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: CC1CN(C)CC(C)N1CCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-{5-chloro-2-[3-(2,6-cis-dimethylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide as a yellow solid. ES+(m/z) 513 (35Cl) and 515 (37Cl) [M(free base)+H].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: CC(C)N1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCN(C(C)C)CC5)c34)cc2Cl)cn1
Yield: 71 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-isopropylpiperazine to give the title compound in 71% yield; NMR Spectrum: 0.91 (d, 6H), 2.39 (br s, 4H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.55 (m, 1H), 2.78 (t, 2H), 4.44 (t, 2H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: C(O)(=[O:3])C.[C:5]1([S:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OO.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[C:14]1([S:13][CH2:12][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O
Reactant: c1ccc(SCSc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=S(CSc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
5 ml of acetic acid was added to 1.538 g of bis(phenylthio)methane, 0.75 ml of an aqueous solution of hydrogen peroxide (concentration: 30%) was added thereto, and then the mixture was stirred for 1 hour at room temperature. After 100 ml of methylene chloride, 6 g of potassium carbonate and a small amount of water were thereto, the resultant mixture was dried with anhydrous sodium sulfate. The product was concentrated under reduced pressure, and then the leavings were separated by means of column-chromatography (silica gel, methylene chloride). Thus 1.585 g of phenyl phenylthiomethyl sulfoxide was obtained as a colorless liquid. The yield was 96.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl.[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CCC>[NH:11]([C:18]1[C:23]([Br:24])=[CH:22][N:21]=[C:20]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=2)[N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Product: NCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
4-Aminobenzylamine (122 mg, 1.0 mmol) and ethereal hydrogen chloride (1.0 M; 1.0 ml, 1.0 mmol) were added to a solution of 4-anilino-5-bromo-2-chloropyrimidine (256 mg, 0.9 mmol) in n-butanol (4 ml) and the mixture was heated at 100° C. for 16 hours. The insoluble solid was filtered off and dissolved in methanol (5 ml). Silica (2 g) was added and volatile material was removed by evaporation. The residue was purified by bond elute chromatography, eluting with 0–4% 2.0 M methanolic ammonia solution in DCM, to give the product (163 mg, 49%): LCMS (MH+): 370, 372; HPLC (RT, System A): 2.04.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:27])[CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Product: COc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
Intermediate 13 (0.0432 mol) was added at room temperature to phosphoryl chloride (150 ml). The mixture was stirred at 100° C. for 3 hours then brought to room temperature. The solvent was evaporated till dryness. The residue was taken up in DCM. The solvent was evaporated. The residue was taken up in DCM. The mixture was poured out into ice water, neutralized with K2CO3 solid and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried under a vacuo, yielding 15.5 g (87%) of intermediate 14. The mother layer was purified by column chromatography over silica gel (eluent: toluene/EtOAc; 93/7; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.7 g, 4%) was crystallized from 2-propanone. The precipitate was filtered off and dried under a vacuo, yielding 0.5 g (3%) of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-methoxyphenyl)-methanone (intermediate 14), mp. 175° C.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.[ClH:18]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:18].[OH:8][C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12]
Reactant: N#Cc1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(F)cc1O
Yield: 74.3 %

Procedure:
A solution of intermediate 134, 2-(benzyloxy)-4-fluorobenzonitrile, (9.03 g, 39.7 mmol) in ethanol (100 mL) and ethyl acetate (100 mL) was stirred with 10% palladium on carbon (1.67 g,) and concentrated hydrochloric acid (12 mL, 144 mmol) under a hydrogen atmosphere (60 psi) for four days. The catalyst was removed by filtration through Celite, and the filtrate was concentrated. The crude product was triturated with ether and the resulting solid collected by filtration to give the title compound (5.24 g, 74% yield) as a pale orange solid. 1H NMR (500 MHz, DMSO-D6) δ ppm: 10.81 (1H, s), 8.18 (3H, s), 7.36 (1H, t, J=7.3 Hz), 6.79 (1H, dd, J=10.8, 2.6 Hz), 6.66 (1H, dt, J=8.5, 2.3 Hz), 3.90 (2H, d, J=5.2 Hz).