Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[CH2:19][CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(#N)C.C(OCC)(=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:14][CH2:13]1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1ccc2[nH]cc(CC3CCN(CCOc4cccc5[nH]ccc45)CC3)c2c1
Yield: 11.4 %

Procedure:
To a solution of 5-fluoro-3-[(4-piperidinyl)methyl]-1H-indole (0.84 g, 3.6 mmol) in acetonitrile (50 mL) was added 4-(2-chloroethoxy)-1H-indole (0.59 g, 3.6 mmol), potassium carbonate (0.48 g) followed by addition of potassium iodide (0.60 g) at room temperature. The reaction mixture was heated to reflux for 5 h and cooled. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride/methanol, 95/5) to 0.45 g (38%) of a white foam. The free base (0.23 g, 0.59 mmol) was dissolved in ethyl acetate, and precipitated with one equivalent of HCl in ether to give the title compound (0.16 g, 62%) as monohydrochloride, 1.0 hydrate: mp 215° C. (dec.); 1H NMR (DMSO, 400 MHz), 1.52-1.59 (m, 2H), 1.81-1.84 (m, 3H), 2.61 (d, 2H), 3.02-3.08 (m, 2H), 3.25-3.30 (m, 6H), 4.46 (t, 2H), 6.44-7.33 (m, 9H), 10.25 (br s, 1H), 10.98 (br s, 1H), 11.14 (br s, 1H); MS (FAB) m/z 392 (M+H)+.
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O.O1CCOCC1>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: Nc1ncns1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h
Yield: 120.3 %

Procedure:
Sodium hydroxide (5.08 g, 130 mmol) was dissolved in water (60 mL) and 1,4-dioxane (300 mL). 1,2,4-Thiadiazol-5-amine (10 g, 100 mmol) was added and the reaction mixture was stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 38 mmol) was added and the reaction mixture was allowed to stir for 3 hours at 20° C. After this time, the reaction mixture was poured into 1N aqueous hydrogen chloride solution (150 mL). This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown solid (13 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(Cl)(Cl)Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Cl)c2c(c1)CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Cl)c2[nH]ccc2c1
Yield: 78.3 %

Procedure:
To a solution of 7-chloro-5-nitroindoline (0.23 g, 1.2 mmol) in 20 mL of acetone was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone until color of the solution turns to dark green. Reaction mixture was concentrated in vacuo providing a dark residue which was subjected to column chromatography (CHCl3, neat) to yield 0.18 g (0.94 mmol, 79%) of the indole.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]=[C:6]([CH3:8])[CH3:7])C.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].N1C=CC=C(C)C=1>CC1C=CC(C)=CC=1>[CH3:7][C:6]1([CH3:8])[CH:5]=[CH:4][C:16]2[CH:15]=[C:14]([C:12]#[N:13])[CH:19]=[CH:18][C:17]=2[O:20]1
Reactant: CCOC(C=C(C)C)OCC
Reactant: N#Cc1ccc(O)cc1
Solvent: Cc1cccnc1
Solvent: Cc1ccc(C)cc1
Product: CC1(C)C=Cc2cc(C#N)ccc2O1

Procedure:
A 500-mL, 3-necked, round-bottomed flask topped with a distilling head, internal temperature probe/argon inlet, and an overhead stirrer was sequentially charged with the title A compound, 1,1-diethoxy-3-methyl-2-butene (26.59 g, 168.00 mmol), p-xylene (300 mL), 4-cyanophenol (15.00 g, 125.92 mmol), and 3-picoline (3.0 mL, 2.870 g, 30.83 mmol). The reaction mixture was rapidly stirred. The internal temperature was rapidly brought up to 115° C. and then slowly raised in order to distill off the ethanol formed during the reaction.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([OH:19])[C@H:6]([OH:20])[C@H:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>NCCO>[OH:19][C@@H:7]1[C:8]2[CH:9]=[CH:10][N:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:12]3[C:13]=2[NH:4][C@H:5]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:6]1[OH:20]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)[C@H](O)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCO
Product: Cc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3

Procedure:
The N-acetyl protecting group is detached from the compound (7R,8R,9R)-10-acetyl-7,8-dihydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine by heating with potassium carbonate in 2-aminoethanol (temp. 70-100° C.). After extractive workup and crystallization, the title compound is obtained as a colourless solid of m.p. 206-209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)=CC=1)([O-])=O>CO>[CH:47]([O:46][C:43]1[CH:44]=[CH:45][C:40]([NH:39][C:38]([N:16]2[CH2:17][CH2:18][CH:13]([C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][N:8]=3)[CH2:14][CH2:15]2)=[O:37])=[CH:41][CH:42]=1)([CH3:49])[CH3:48]
Reactant: COc1ccc2c(C3CCNCC3)ncnc2c1
Reactant: CC(C)Oc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(C3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)ncnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Solid KOH (224 mg, 4 mmol) was added to a solution of 4-(7-chloro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (29a; 41 mg, 0.1 mmol), prepared as described in Example 29, in anhydrous MeOH (1 mL). The mixture was stirred at 100° C. for 3 h. It was then cooled to rt and concentrated in vacuo. The residue was dissolved in DCM and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (31a). This was dissolved in 2 mL of 3M HCl/MeOH was stirred at rt for 1 h and then concentrated in vacuo to obtain crude 4-(7-methoxy-quinazolin-4-yl)-piperidine (31b) as a di-HCl salt. To a suspension of (31b) in anhydrous MeOH (2 mL), was added DIEA (45 μL, 0.25 mmol) followed by (4-isopropoxy-phenyl)-carbamic acid 4-nitro-phenyl ester (48 mg, 0.15 mmol), as prepared in Example 1a, and the mixture was stirred at rt for 1 h. It was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 1% MeOH/DCM) to obtain 5.4 mg (13% overall yield from 29a) of pure 4-(7-methoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-isopropoxy-phenyl)-amide. 1H-NMR (300 MHz, CDCl3): δ 9.14 (s, 1H), 8.06 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 3H), 6.84 (d, 2H), 6.30 (s, 1H), 4.48 (m, 1H), 4.26 (m, 2H), 3.99 (s, 3H), 3.69 (m, 1H), 3.14 (m, 2H), 2.23-2.05 (m, 2H), 2.03-1.92 (m, 2H), 1.31 (d, 6H). LC/MS (ESI): calcd mass 420.2, found 421.4 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:40]4[CH2:41][CH2:42][CH:37]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:38][CH2:39]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(N2CCCCC2)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 172 mg (1.02 mmol) of 4-piperidinopiperidine in 5.0 ml dimethylformamide was stirred at room temperature for 4 hr and at 60° C. for 1 hr. After the mixture was cooled, the suspension was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil and purified by preparative TLC to yield 100 mg (40%) yellow solid: mp 140-144° C.
Reaction SMILES: [P:1]([O:5][CH2:6][CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])([OH:4])([OH:3])=[O:2].C(O[N:20]([CH3:26])[CH2:21][C:22](=C=O)[OH:23])C1C=CC=CC=1.[H][H]>O1CCOCC1.O.[Pd]>[P:1]([O:5][CH2:6][CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])([OH:3])([OH:4])=[O:2].[CH3:26][NH:20][CH2:21][CH2:22][OH:23]
Reactant: [H][H]
Reactant: CN(CC(O)=C=O)OCc1ccccc1
Agent: [Pd]
Agent: C[N+](C)(C)CCOP(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CNCCO

Procedure:
8 g of N-benzyloxy carbonyl-N-methyl-2-aminoethanol phosphocholine are dissolved in 60 ml of dioxane and 15 ml of water; the solution is mixed with 0.8 g of 10% palladium active carbon and the reaction mixture hydrogenated with hydrogen. After the H2 -absorption has terminated, the solution is filtered and the filtrate reduced in vacuo to dryness.
Reaction SMILES: [C:1]1([N:7]2[C:11](O)=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19].Cl>>[C:1]1([N:7]2[C:11]([Cl:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nnn(-c2ccccc2)c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Product: CCOC(=O)c1nnn(-c2ccccc2)c1Cl
Temperature: 70 °C

Procedure:
11.65 g of 20A was mixed with 13.8 g of phosphorus pentachloride, and the mixture was slowly heated to ca. 70° C., when vigorous reaction occurred. When reaction had subsided, heating was continued until evolution of hydrogen chloride ceased (about 1 hour), after which phosphoryl chloride was removed in vacuo, and the residue chromatographically purified to yield 1-phenyl-4-ethoxycarbonyl-5-chloro-1,2,3-triazole (20B), as a solid, m.p.: 80°-81° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:3]5[N:2]([CH3:1])[CH:6]=[C:5]([CH3:7])[CH:4]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cc(C(=O)O)n(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)c1
Yield: 82 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrrole-2-carboxylic acid (225 mg, 1.62 mmol), tetrahydrofuran (7 mL), oxalyl chloride (212 μL, 1.67 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (228 mg, 82%) was obtained as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].CN(C=O)C.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][C:37]3[C:42]([N:43]=2)=[CH:41][CH:40]=[C:39]([C:44]2([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:46][CH2:45]2)[N:38]=3)=[C:31]([F:53])[CH:30]=1>C1COCC1.CCOC(C)=O>[C:18]([NH:17][C:11]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[S:36][C:37]3[C:42]([N:43]=2)=[CH:41][CH:40]=[C:39]([C:44]2([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH2:45][CH2:46]2)[N:38]=3)=[C:31]([F:53])[CH:30]=1)([C:10]([O:9][CH2:7][CH3:8])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:20])[CH3:19]
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)(NC(C)=O)C(=O)OCC
Temperature: 80 °C

Procedure:
In a sealable bottle, sodium tert-butoxide (0.120 g, 1.25 mmol) was added to a mixture of acetamidomalonic acid diethyl ester (0.272 g, 1.25 mmol) in THF (10.00 ml)/DMF (2.00 ml). The reaction was heated to 80° C. for 20 min., cooled to ambient temperature, and a solution of 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.500 g, 1.14 mmol) in THF 4 ml was added slowly dropwise. The resulting mixture was heated to reflux (90 deg. C.) for 1.5 h, and the color changed from orange to yellow. The reaction was cooled, poured over ice water, and treated with EtOAc. The organic layer was washed with water, NaCl, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, 40 g column, 10-30% EtOAc/hexanes, followed by 30-50% (3% Et3N in EtOAc)/hexanes provided diethyl 2-acetamido-2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)malonate. MS (ESI) m/z: calculated: 575.2; Observed: 576.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: C=C(C)CBr
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(=O)OC)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
In a 200 ml pear flask were added methyl 4-bromo-3-hydroxybenzoate (3.5 g, 15 mmol), potassium carbonate (4.2 g, 30 mmol) and tetrabutylammonium iodide (0.084 g, 0.23 mmol) in DMF (35 ml) to give a suspension. At 0° C. was added 3-bromo-2-methylprop-1-ene (1.7 ml, 17 mmol) to this mixture, which was then stirred at room temperature for ˜16 h. The reaction mixture was partitioned between brine and ether, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the crude product methyl 4-bromo-3-(2-methylallyloxy)benzoate (4.3 g, 99% yield) as a light yellow oil. 1H NMR (CHLOROFORM-d) δ: 7.61 (d, J=8.1 Hz, 7H), 7.53 (d, J=1.5 Hz, 7H), 7.50 (dd, J=8.1, 1.8 Hz, 7H), 5.20 (d, J=1.0 Hz, 7H), 5.02-5.07 (m, 7H), 4.56 (s, 2H), 3.92 (s, 3H), 1.87 (s, 3H); ESI-MS: m/z 242.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[N:33]12CCN(CC1)C[CH2:34]2>O.CS(C)=O.CC(O)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[N:27]=[C:26]([C:34]#[N:33])[N:25]=[CH:24][N:23]=3)[CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CN2CCN1CC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Nc3ncnc(Cl)n3)c2)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(Nc3ncnc(C#N)n3)c2)cc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A mixture of [3′-(4-chloro-[1,3,5]triazin-2-ylamino) -biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester (55 mg), potassium cyanide (22 mg) and 1,4-diazabicyclo[2,2,2]octane (4 mg) in water (0.3 ml) and DMSO (1.3 ml) is stirred at 5° C. for 1.5 h. This mixture is acidified with 3 drops of AcOH, quenched with brine and extracted three times with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated and the crude product is purified on silica (4 g) with cyclohexane/EtOAc=4/1 to afford pure [3′-(4-cyano-[1,3,5]triazin-2-ylamino)-biphenyl-4-ylmethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: COC1C=CC2C3C=C4C=CC(OC)=CC4=C(O)C=3CC=2C=1.[CH3:23][O:24][C:25]1[CH:45]=[CH:44][C:28]2[C:29]3[C:38]([CH2:39][CH2:40][C:27]=2[CH:26]=1)=[C:37]([OH:41])[C:36]1[C:31](=[CH:32][CH:33]=[C:34]([O:42][CH3:43])[CH:35]=1)[CH:30]=3.[Cl:46]C1C(=O)C(Cl)=C(Cl)C(Cl)(Cl)C=1Cl.O>CN(C=O)C>[CH3:23][O:24][C:25]1[CH:45]=[CH:44][C:28]2[C:29]3[C:38]([CH2:39][CH2:40][C:27]=2[CH:26]=1)=[C:37]([OH:41])[C:36]1[C:31](=[CH:32][CH:33]=[C:34]([O:42][CH3:43])[CH:35]=1)[CH:30]=3.[Cl:46][C:30]1[C:31]2[C:36]([C:37]([OH:41])=[C:38]3[C:29]=1[C:28]1[CH:44]=[CH:45][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH2:40][CH2:39]3)=[CH:35][C:34]([O:42][CH3:43])=[CH:33][CH:32]=2
Reactant: O=C1C(Cl)=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Agent: COc1ccc2c(c1)CCc1c-2cc2ccc(OC)cc2c1O
Agent: COc1ccc2c(c1)Cc1c-2cc2ccc(OC)cc2c1O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2c(Cl)c2ccc(OC)cc2c1O
Temperature: 40 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
The compound 3,9-dimethoxy-7-hydroxy-5,6-dihydro-benz[a]anthracene (compounds 23) was prepared analogously to compound 16 in example 5. To a solution of 600 mg of 23 in 10 ml of DMF was added in portions 600 mg of 2,3,4,4,5,6-hexachlorocyclohexa-2,5-dien-1-one. The mixture was then stirred at 40° C. for 4 hr. Then the reaction was poured into water and the product extracted with ethyl acetate. The crude material was passed through a silicagel column (hept./eth.ac.) and finally triturated with heptane-diisopropyl ether to provide 280 mg of 24 as orange crystals; Mp 140-141° C., Rf 0.28 (hept./eth.ac. 7/3) starting material Rf 0.30.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10](C)([O-])[CH3:11].[K+].C(Br)C=C.Cl>CN(C)C=O.O>[CH2:11]([C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:10]=[CH2:9]
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C=CCBr
Product: C=CCC1(CO)CCCCC1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of cyclohexane carbaldehyde (2.24 g) in N,N-dimethylformamide (30 mL) were added potassium tert-butoxide (2.70 g) and allyl bromide (4.33 mL) under ice cooling. The solution was stirred under ice cooling for 30 minutes. Water and 1N hydrochloric acid were then added to the solution, and it was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in ethanol (60 mL) was added sodium borohydride (567 mg) under ice cooling. The solution was stirred at room temperature for 16 hours. Acetic acid was added to the solution, and it was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium bicarbonate solution, and it was extracted with diethyl ether. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:1) to give the title compound (1.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].O>C1CCN2C(=NCCC2)CC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C(O)CNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 150 °C

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) and glycine (4.8 g, 0.06 ml) in DBU (100 ml) is heated at 150° C. under an atmosphere of argon for 40 hours. The still hot reaction mixture is poured into water. After washing the aqueous phase with ethyl acetate the pH is adjusted to 5 by adding citric acid. The resulting precipiate is filtered and recrystallized from dimethylformamide/ethanol to give the product in form of yellow crystals, m.p. 136–138° C. (with decomposition).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:21])[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[O:13][C:12]([CH3:23])([CH3:22])[CH2:11][C:10]2=O>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([Cl:21])[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[O:13][C:12]([CH3:23])([CH3:22])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)CC2=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)Oc1c(Br)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 18.8 mL, 37.6 mmol), 6-bromo-8-chloro-7-isopropoxy-2,2-dimethyl-chroman-4-one, (Compound 11, 2.6 g, 7.5 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(]-pyrimidinone (DMPU, 4.5 mL, 37.6 mmol) in THF was reacted to afford the title compound as a yellow oil after purification by flash chromatography (silica gel, 5% to 10% ethyl acetate in hexanes).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([O:14][C:15](=[O:46])[N:16]([CH3:45])[C@@H:17]([C:29](=[O:44])[NH:30][C@H:31]([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]C=C)[CH:32]([CH3:34])[CH3:33])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl>[CH:1]1[C:13]2[CH:12]([O:14][C:15](=[O:46])[N:16]([CH3:45])[C@@H:17]3[CH2:18][C:19]4=[CH:20][CH:21]=[C:22]([CH:23]=[CH:24]4)[O:25][CH2:26][CH:27]=[CH:28][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:29]3=[O:44])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCCCCOC[C@@H](NC(=O)[C@@H](Cc1ccc(OCC=C)cc1)N(C)C(=O)OC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COCCCCCC=CCOc2ccc(cc2)C[C@@H](N(C)C(=O)OC2c3ccccc3-c3ccccc32)C(=O)N1
Yield: 90.6 %

Procedure:
A solution of 1.01 g (1.61 mmol) of 9H-fluoren-9-yl-methyl[(R)-2-(4-allyloxyphenyl)-1-((S)-1-hept-6-enyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate and 0.15 g (0.24 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 460 ml of dichloromethane was stirred at 40° C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 0.87 g of the desired compound was obtained as a colorless solid.