Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:14]2)=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36](C(O)=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=3[O:30][CH3:31])[CH2:14]2)=[O:22])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(4-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-5-chloro-2-methoxybenzamide (1.35 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.60 g) to give 4-amino-N-(1-(4-(4-amino-5-chloro-2-methoxybenzoylamino)butyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[C:18](=[O:31])[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>FC(F)(F)C(O)=O>[CH3:1][N:2]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH2:32][C:33]([OH:35])=[O:34])[C:18](=[O:31])[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)c1ccccc1N(CC(=O)O)C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 96.3 %

Procedure:
2-{N-[2-(N-Methylanilino)carbonylphenyl]-2-phthalimidoacetamideo}acetic acid may be prepared in the following manner: a solution of tert-butyl 2-{N-[2-(N-methylanilino)carbonylphenyl]-2-phthalimidoacetamido]acetate (7.9 g) in trifluoroacetic acid (30 cc) is stirred at a temperature in the region of 20° C. for 24 hours and then poured into water (50 cc). The aqueous phase is extracted with dichloromethane (3×250 cc). The organic phases are combined, washed with water (2×150 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. The residue is treated with petroleum ether (100 cc) and the insoluble product is separated by filtration and dried under reduced pressure (15 kPa) at 30° C. 2-{N-[2-(N-Methylanilino)carbonylphenyl]-2-phthalimidoacetamido}acetic acid (6.8 g) is thereby obtained in the form of an amorphous solid, which is used without further treatment in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CO>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([CH3:16])=[CH:13][C:12]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=C(C)Nc1ccc(NC(C)=O)cc1
Temperature: 5 °C
Yield: 46.8 %

Procedure:
A suspension of 4-aminoacetanilide (2) (253 g, 1.68 mol) and methyl acetoacetate (215 g, 1.85 mol) in MeOH (0.75 L) was heated to reflux. The resulting solution was held at reflux for 16 h and then cooled to 5° C. The resulting off-white precipitate was filtered and washed with MTBE (3×200 mL) to give butenoate 3 (195 g, 47% yield). The mother liquor was concentrated in vacuo and filtered to give a second crop of 3 as pale pink solids (141 g, 34% yield, 81% overall yield). 1H NMR (DMSO) δ 10.22 (s, 1 H), 9.97 (s, 1 H), 7.57 (d, 2 H), 7.11 (d, 2 H), 4.65 (s, 1 H), 3.56 (s, 3 H), 2.04 (s, 3 H), 1.94 (s, 3 H); 13C NMR (DMSO) δ 169.64, 168.07, 159.33, 136.48, 133.55, 124.52, 119.44, 84.47, 49.77, 23.81, 19.68.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:15]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[S:17][C:18]=5[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.CO.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]1([O:48][CH2:47]1)[CH3:46]>>[CH:28]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH:3]6[CH2:4][N:1]([CH2:44][C:45]([CH3:47])([OH:48])[CH3:46])[CH2:2]6)[CH:9]=5)[CH:32]=[CH:31][C:13]=4[C:14]=3[N:15]=2)=[N:26][C:25]([CH3:27])=[N:24]1)([CH3:29])[CH3:30]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1
Reactant: CC1(C)CO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(CC(C)(C)O)C5)c4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a slurry of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.232 g, 0.000519 mol) in methanol (3.0 mL, 0.074 mol) was added N,N-Diisopropylethylamine (0.108 mL, 0.000623 mol) then isobutylene oxide (0.330 mL, 0.0037 mol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and purified by reverse-phase HPLC to give 480 (24.3 mg) as a colorless solid. MS(ESI+) 520.2. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.31 (d, J=8.3, 1H), 8.01 (s, 1H), 7.47 (dd, J=8.3, 1.8, 1H), 7.35 (d, J=1.8, 1H), 5.86-5.68 (m, 1H), 4.97 (p, J=6.9, 1H), 4.39 (t, J=5.0, 2H), 4.11 (s, 1H), 3.79 (dd, J=8.0, 7.3, 2H), 3.49 (dd, J=8.0, 6.8, 2H), 3.44 (t, J=5.0, 2H), 2.44 (s, 2H), 2.32 (s, 3H), 1.53 (d, J=6.6, 6H), 1.08 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:17]([NH:19][CH2:20][CH2:21]O)=[S:18])[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[I-].C(C[P+](C)(C)C)#N>C(#N)CC>[S:18]1[CH2:21][CH2:20][N:19]=[C:17]1[NH:16][CH:10]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccs2)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(C)cc(CC(NC2=NCCS2)c2cccs2)c1
Temperature: 90 °C
Yield: 0.1 %

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-1-thiophen-2-yl-ethyl]-3-(2-hydroxy-ethyl)-thiourea (0.30 g) from example 6 and diisopropyethylamine (0.16 g) in propionitrile (10 ml) was added cyanomethyl-trimethyl-phosphonium iodide (0.27 g, prepared according to Tetrahedron 2001, 57, 5451-54). The reaction mixture was heated up to 90° C. for 72 h. Extraction with ethyl acetate, washing with potassium carbonate solution and water followed by drying and evaporation of the solvent yielded 0.27 mg (95%) of the title compound as brownish oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:30]=[C:31]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]1[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:39]([CH2:38][CH2:37][N:32]2[C:33](=[O:36])[CH2:34][CH2:35][C:31]2=[O:30])(=[O:40])=[O:41])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: O=C1CCC(=O)N1CCS(=O)(=O)Cl
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)CCN4C(=O)CCC4=O)c3c2)C(C#N)=C(C)N1

Procedure:
The title compound was prepared following the procedure described for Example 1 using 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) and 173 mg (0.77 mmol) 2-(2,5-dioxopyrrolidin-1-yl)ethane-sulfonyl chloride. Yield: 20 mg (17% of th.).
Reaction SMILES: Br[CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([NH:11][CH2:12][C:13]#[N:14])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CC(C)=O>[C:13]([CH2:12][NH:11][C:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][S:28][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[O:10])#[N:14]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-N-cyanomethylcyclohexanecarboxamide (262 mg, 1 mmol) and cesium carbonate (331 mg, 1.02 mmol) were weighed into a 15 mL test tube fitted with a stir bar and vented cap and then acetone (3 mL) and 4-fluorobenzenethiol (106 μL, 1.01 mmol) were added sequentially to the test tube. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL). The reaction mixture was filtered through Celite™ and the filter funnel and Celite™ were washed with hot acetone (25 mL). The combined filtrate and wash were concentrated on a rotary evaporator and product was purified from the residue by chromatography on 40 cm3 of silica gel in a 2×13 cm column with 9:1 dichloromethane:ethyl acetate eluent. The product fractions were concentrated on a rotary evaporator and the residue dried under high vacuum to give trans-N-cyanomethyl-2-(4-fluorophenylsulfanylmethyl)-cyclohexanecarboxamide as a waxy white solid. 1H NMR (DMSO-d6): δ 8.64 (1H, t), 7.33 (2H, m), 7.14 (2H, m), 4.13 (2H, d), 2.96 (1H, dd), 2.57 (1H, dd), 2.05 (2H, m), 1.70 (4H, m), 1.15 (4H, m). MS [ESI, (M−H)−] m/z=305.0 amu.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].OS(O)(=O)=O.[BrH:16].CC(N=NC(C#N)(C)C)(C#N)C.OO>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:5]([Br:8])=[CH:6][CH:7]=1)[CH2:9][Br:16]
Reactant: Br
Reactant: Cc1c(Br)ccc(Br)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Cc1c(Br)ccc(Br)c1CBr
Temperature: 70 °C
Reaction time: 14 h

Procedure:
183.2 g (0.65 mol) of 3,6-dibromo-1,2-xylene are initially charged in 750 ml of chlorobenzene, and 2 g of conc. H2SO4 and 270.7 g (1.57 mol) of 47% strength hydrobromic acid are then added. The reaction mixture is heated to 70° C. and 0.3 g of AIBN are added. Over 14 h, 237.7 g (0.7 mol) of a 10% strength solution of hydrogen peroxide are added at 75-77° C., the mixture is stirred for another 120 min., washed 2× with 250 ml of water and once with 250 ml of saturated sodium bicarbonate solution, and the chlorobenzene is then distilled off.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Br[C:12]1[CH:13]=[CH:14][C:15]([N+:25]([O-:27])=[O:26])=[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:13]=[CH:14][C:15]([N+:25]([O-:27])=[O:26])=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]3)[CH:17]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Reactant: COC(=O)C1CCOCC1
Product: COC(=O)C1(c2ccc([N+](=O)[O-])c(N3CCC(C)CC3)c2)CCOCC1

Procedure:
The title compound is prepared by the procedure of Example 16, step (a) using tetrahydro-pyran-4-carboxylic acid methyl ester and 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (US 2005131022 A1).
Reaction SMILES: [ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: O=C(O)CC1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 8 parts of ethyl 1-(phenylmethyl)-4-piperidineacetate hydrochloride and 80 parts of a dilute hydrochloric acid solution was stirred and refluxed for 4 hours. After cooling, the reaction mixture was evaporated. The residue was washed with 2-propanone and the solvent was evaporated again. The solid residue was washed with 2-propanone, filtered off and dried, yielding 6 parts of 1-(phenylmethyl)-4-piperidineacetic acid hydrochloride; mp. 137°-145° C. (2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH2:31]([N:33]([CH2:45][CH3:46])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH2:43][CH3:44])[CH3:32]>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>[Si:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=2)=[CH:3][C:2]=1[C:37]1[CH:38]=[CH:39][C:34]([N:33]([CH2:45][CH3:46])[CH2:31][CH3:32])=[C:35]([CH2:43][CH3:44])[CH:36]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCc1cc(B(O)O)ccc1N(CC)CC
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc(N(CC)CC)c(CC)c3)c2)cc1
Yield: 39.4 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1.4 g (2.9 mmol) of ethyl 3′-bromo-4′-[3-(tert-butyldimethylsilanyloxy)propoxy]biphenyl-4-carboxylate (obtained in Example 5b) with 900 mg of 4-diethylamino-3-ethylphenylboronic acid (4 mmol) in the presence of tetrakis(triphenylphosphine)palladium, 674 mg of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-4″-diethylamino-3″-ethyl[1,1′;3′,1″]terphenyl-4-carboxylate (yield=39%) are obtained in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[Br:1][C:2]([Br:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)Cl
Yield: 50.7 %

Procedure:
In a manner similar to Example 13A, the reaction of 13.0 g (0.0436 mole) of (±)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid, 50 ml of toluene, and 11.1 g (0.0873 mole) of oxalyl chloride gave 7.0 g of (±)-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH-:1].[K+].[N:3]1([C:8]2[C:17]3[C:12](=[N:13][C:14](Cl)=[C:15]([Cl:18])[N:16]=3)[N:11]=[C:10](Cl)[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O.O1CCCC1>[Cl:18][C:15]1[N:16]=[C:17]2[C:12](=[N:13][C:14]=1[OH:1])[N:11]=[C:10]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[N:9]=[C:8]2[N:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1nc2nc(N3CCNCC3)nc(N3CCCC3)c2nc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
a)+b) 460 μl (0.82 mmol) of a 10% solution of potassium hydroxide in water is added dropwise to a solution of 250 mg (0.82 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloro-pteridine in 15 ml of tetrahydrofuran cooled to −10° C. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for approx. another 16 hours. Then a solution of 318 mg (3.69 mmol) piperazine in 10 ml of tetrahydrofuran is added and the mixture is refluxed for approx. 16 hours. Then the solvent is eliminated in vacuo, the residue is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography. Yield 50 mg (14% of theoretical)
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH3:43][C:44](=O)[CH3:45]>>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[O:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:1][C:44]3([CH3:45])[CH3:43])[CH2:10][CH2:11]2)=[CH:23][CH:24]=1
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(C)=O
Agent: O=C(O)C(=O)O
Product: CC1(C)Nc2ccccc2C(=O)N1CCN1CCC(Oc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 77 %

Procedure:
A mixture of 5 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinyl]ethyl]-benzamide, 80 parts of 2-propanone and 1.9 parts of ethanedioic acid was stirred for 1 hour at reflux temperature. After cooling, the product was filtered off and dried, yielding 4.8 parts (77%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-1-piperidinyl]ethyl]-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone ethanedioate (1:1); mp. 166.5° C. (485).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13](C3C([N+]([O-])=O)=C(S([O-])(=O)=O)C=CC=3)[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1.C(O)(=O)C.[BrH:48].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([Br:48])[CH2:12]2)=[O:10])=[C:4]([C:36](=[O:43])[NH:37][CH:38]([CH:40]2[CH2:42][CH2:41]2)[CH3:39])[CH:3]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(c2cccc(S(=O)(=O)[O-])c2[N+](=O)[O-])=NN1c1ncccc1Cl)C1CC1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Reaction time: 1 h

Procedure:
400 mg of 5-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenylcarbamoyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazol-3-yl2-nitrobenzene sulfonate was dissolved in 0.7 mL of acetic acid, and 0.3 mL of a 33 mass % hydrogen bromide acetic acid solution was dropwise added, followed by stirring for about one hour. After completion of the reaction, ethyl acetate, water and 2 mL of 1 N sodium hydroxide were added, followed by stirring and extraction with ethyl acetate. Then, concentration under reduced pressure was carried out to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/2) to obtain 310 mg of the desired product in a paste form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH2:13]([N:15]([CH2:30]C)[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])C>>[CH3:30][N:15]([CH3:13])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)C(=Cc1cc(C)c(C(=O)NCCCN(C)C)[nH]1)C(=O)N2
Yield: 39 %

Procedure:
5-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 80 mg (39%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[Br:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14]([CH2:29][CH2:30][CH2:31]Br)([CH2:25][CH2:26][CH2:27]Br)[C:13]=2[CH:12]=1>COCCOC>[Br:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14]([CH2:25][CH2:26][CH2:27][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)([CH2:29][CH2:30][CH2:31][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]3)[C:13]=2[CH:12]=1
Reactant: BrCCCC1(CCCBr)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CC1(C)OCC(CO)O1
Solvent: COCCOC
Product: CC1(C)OCC(COCCCC2(CCCOCC3COC(C)(C)O3)c3cc(Br)ccc3-c3ccc(Br)cc32)O1
Reaction time: 0.33 h

Procedure:
Potassium terbutylate (3.0 g, 26.7 mmoles) are added, in an inert atmosphere, to a solution of solketal (3.5 g, 26.7 mmoles) in 50.0 ml of 1,2-dimethoxyethane. After 20 minutes, 5.0 g of 2,7-dibromo-9,9-bis(3′-bromopropyl)fluorene (5.0 g, 8.9 mmoles) dissolved in 15.0 ml of 1,2-dimethoxyethane are added.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:36])([CH3:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1C=CC(C#N)=CC=1)[CH3:6].[OH-].[K+].O.[C:40](O)(=O)[CH2:41][C:42]([CH2:47][C:48](O)=O)([C:44]([OH:46])=[O:45])O>C(O)CO>[OH:1][C@H:2]([CH2:21][NH:22][C:23]([CH3:35])([CH3:36])[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH2:3][O:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:40]=[CH:41][C:42]([C:44]([OH:46])=[O:45])=[CH:47][CH:48]=1)[CH3:6]
Reactant: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C#N)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC(OC[C@H](O)CNC(C)(C)Cc1ccc2ccccc2c1)c1ccccc1-c1ccc(C(=O)O)cc1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
2′-[1-[(2R)-2-Hydroxy-3-[[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino]propoxy]ethyl]biphenyl-4-carbonitrile (1.0 g) obtained in Example 7, Step 2 was dissolved in ethylene glycol (15 ml). Potassium hydroxide (2.76 g) was added and the mixture was stirred overnight at 160° C. The reaction mixture was allowed to return to room temperature, a small amount of water was added and 10% aqueous citric acid was added to adjust the mixture to pH 4-5. The precipitated solid was collected by filtration to give the title compound (924 mg).
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH3:24])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH:25]=[CH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:7][C:6]=2[N:5]=1>[Pd].C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH3:24])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:7][C:6]=2[N:5]=1
Reactant: COCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COCc1nc2c(N)nc3cc(CCS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (200 mg), methanol (12.5 mL), ethanol (12.5 mL) and 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (750 mg, 1.85 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was sequentially filtered through a 0.2 micron PTFE membrane filter, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 195 mg of 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 210-212° C.