Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8][O:7][C:6]=2[CH:21]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>ClCCl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH2:13][C@H:9]1[CH2:8][O:7][C:6]2[CH:21]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: Cc1ccc2c(c1)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
(S)-tert-butyl 8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (2.50 g, 8.55 mmol, Eq: 1.00) was dissolved in dichloromethane (DCM, 10 mL) at 0° C. and TFA (10 mL) was added. The mixture was stirred at 0° C. for 1.5 h and concentrated to give the title compound (2.69 g, 103%) which was used without purification.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(N(C2CCCCC2)[C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[C:28](C)[CH:27]=2)CCCC1>C1COCC1>[C:1]([N:5]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC1CCCCC1
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C. to 5° C.) stirred solution of N-tertbutyl-N-cyclohexyl amine (3.73 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in dry THF (50 mL) is added dropwise a solution of acid chloride (5.0 g, 23 mmol) in THF (20 mL). The reaction is stirred at room temperature overnight and worked up in the same manner as for 4-bromo-3-methylbenzoic acid N-cyclopentyl-N-cyclohexyl amide. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-methyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (307 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 52%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.CS(O[CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O>>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCOc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)CCCOc1cccc2c1Cc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 35 %

Procedure:
Using ethyl 4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]butyrate and 2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 35%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[N+](C)([O-])=O.Cl>CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([OH:27])[C:5]2[CH:11]=[C:10]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(N)nc(O)c3c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Reaction time: 1 h
Yield: 96 %

Procedure:
Thirty-four milligrams of 2-amino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 15 ml of nitromethane which has been saturated with hydrogen chloride gas at 0° C. The mixture is stirred for 1 hour. Anhydrous ether is added and the solid filtered to give 27.6 mg (62%) of 2-amino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish solid: m.p. >260° C.; NMR (DMSO-d6, 80 MHz) delta 7.71 (d, 2H, J=8.4 Hz), 8.00 (d, 2H, J=8.4 Hz), 8.40 (d, 1H, J=2.3 Hz), 8.75 (d, 1H, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:25]=[O:26])C1C=CC=CC=1.Cl>C1COCC1.O>[CH:25]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7])=[O:26]
Reactant: CNC(=O)c1ccc(Cl)cc1
Reactant: CN(C=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(Cl)cc1C=O
Temperature: 0 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-N-methyl-benzamide (3.1 g) in THF (30 mL) was added n-butyl lithium (30.1 mL of 2.5M hexane solution) and the solution refluxed for 45 min. The solution was then cooled to 0° C. and N-methylformanilide (9.27 mL) added dropwise over 2 min. The solution was then refluxed for 2 h, then cooled to ambient temperature, water (80 mL) added and the solution acidified to pH 1 with 2M HCl. The solution was then extracted three times with ethyl acetate (3×50 mL), washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified on silica by flash chromatography to afford the sub-titled product as a pale yellow solid (2.13 g; 59%). 1H NMR (400 MHz, CDCl3) δ 2.90 (3H, s), 4.25 (1H, d, J) 5.60 (1H, d, J), 7.35 (2H, s), 7.60 (1H, s) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].[CH2:14]1[O:16][CH2:15]1.[NH4+].[Cl-]>CCOCC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH:15]([OH:16])[CH3:14])([CH3:3])[CH3:2]
Reactant: C1CO1
Reactant: CC(C)c1cccc(C(C)C)c1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1C(C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,6 diisopropylbromobenzene (see J. Org. Chem., 42(14):2426-2431 (1977) forpreparation) (30 g, 124.4 mmol) was added to a suspension of Li powder (1.9g, 273.6 mmol) in ether (100 mL) heated under reflux, the heating was continued for another 4 hours, cooled, and the mixture was poured into ethylene oxide which was precooled to -78° C. The mixture was warmed slowly to room temperature, saturated NH4Cl solution was added slowly with caution, the ether layer was separated and washed with brine, dried over MgSO4, filtered, and the solvent was evaporated to dryness. After column chromatography (3:1 hexane:ethyl acetate) pure 2,6-diisopropylphenylethanol was obtained (17 g, 6.3%); NMR (CDCl3): δ 1.2-1.3 (m, 12H) , 3.05 (t, 2H), 3.15-3.35 (m, 2H), 3.7-3.8 (t, 2H), 7.1-7.3 (m, 3H) ppm.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][C:9]=1[F:16])#[N:7]>CN(C)C=O>[CH2:1]([NH:5][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([C:6]#[N:7])=[C:9]([F:16])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNCc1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
4.64 ml n-butylamine was dissolved in 30 ml dimethylformamide. 667 mg commercially available 4-cyano-3-fluorobenzylbromide, dissolved in 10 ml dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for thirty minutes. The solvent was removed in vacuo and the residue purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=1:4=>ethyl acetate:methanol=4:1 to obtain 360 mg 4-Butylaminomethyl-2-fluoro-benzonitrile.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]1([C:18]2[S:19][CH:20]=[C:21]([C:23]([N:25]3[CH2:30][C:29]4([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[O:28][CH2:27][CH2:26]3)=[O:24])[N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][C:29]2([O:28][CH2:27][CH2:26][N:25]([C:23]([C:21]3[N:22]=[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[S:19][CH:20]=3)=[O:24])[CH2:30]2)[CH2:31][CH2:32]1
Reactant: OCCCCCCCCCBr
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-bromo-1-nonanol (0.346 g) in MeCN (3 mL) was added to solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.355 g) and triethylamine (0.288 mL) in MeCN (7 mL). The resulting mixture was stirred at 60° C. under argon for 17 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine (×2), dried over sodium sulphate, filtered and evaporated in vacuo. The yellow oil was purified by silica gel chromatography eluting with 0-7% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.378 g.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4].[CH3:28][NH2:29]>C(O)CCC>[CH3:28][NH:29][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Solvent: CCCCO
Product: CNC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
A solution of 4 g of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized to yield the 1-[7-(N-methylcarbamoyl)heptyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[C:10]([Br:17])[CH:9]=2)=[O:5])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[C:10]([Br:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC)c(Br)cc2[nH]1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
The solution of 8.30 g (27.8 mmol) 6-bromo-5-methoxy-1H-indole-2-carboxylic acid ethyl ester (prepared according to J. Org. Chem. 1974, 39, 3580) in 160 mL dichloromethane was cooled to −78° C. At this temperature, 55.7 mL boron tribromide (55.7 mmol; 1M solution in dichloromethane) were added. The solution was allowed to warm to room temperature and after 30 min. the solution was poured on 10% aqueous sodium bicarbonate solution, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with n-hexane:ethyl acetate (2:1 v/v) as eluant to give 5.7 g (72%) of the product as a light yellow solid.
Reaction SMILES: [NH2:1]/[C:2](=[C:5](\[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)/[C:6]#[N:7])/[C:3]#[N:4].S(=O)(=O)(O)O.[CH2:23](O)C>C(OC(OCC)OCC)C>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:8]1[C:5]([C:6]#[N:7])=[C:2]([C:3]#[N:4])[N:1]=[CH:23]1
Reactant: CCO
Reactant: N#C/C(N)=C(\C#N)NCc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(OCC)OCC
Product: N#Cc1ncn(Cc2ccc(Cl)c(Cl)c2)c1C#N

Procedure:
2-Amino-3-(3,4-dichlorobenzylamino)maleonitrile (10.7 g) was heated on a steam bath in a mixture of ethanol (4 ml) and triethylorthoformate (12 g) containing concentrated sulphuric acid (0.02 ml) for 1 hour. The solution was evaporated to dryness to give a semi-solid, which was crystallised from ethanol (50 ml) to give 1-(3,4-dichlorobenzyl)-4,5-dicyanoimidazole (3.0 g), m.p. 131°-132.5° C., as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][S:19][C:13]=3[CH:12]2[CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(Cl)Cl.CO.[NH4+].[OH-]>>[CH2:20]([CH:12]1[C:13]2[S:19][CH:18]=[CH:17][C:14]=2[CH2:15][CH2:16][N:11]1[CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:25][CH:24]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCC1c2sccc2CCN1CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Yield: 80 %

Procedure:
Prepared by Method F using the aminobenzene from Example 15 and methanesulfonyl chloride. The product was isolated as a white solid after flash silica gel chromatography using CH2Cl2 /Methanol/NH4OH (97.5/2.25/0.25 to 95.75/4/0.25). This material was recrystallized from EtOAc/ether to afford the title compound as an near-white solid (80%); mp 98°-105° C.; IR (KBr) 3420, 2930, 1635, 1610, 1553, 1505, 1340, 1310 and 1155 cm-1.
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[C:33]1(C)[C:34]([CH:39]=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH:34]1([CH:39]([OH:40])[C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]1
Reactant: Cc1ccccc1C=O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1
Yield: 85.4 %

Procedure:
By using a method similar to that described in Example 22, but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from o-tolualdehyde (5.78 g), 4-dimethylamino-1-(2-methylphenyl)-2-phenyl-2-buten-1-ol (Z) hydrochloride (10.2 g) is obtained in the form of a white powder melting at 204° C. after recrystallisation from ethanol (100 cc).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 19 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and thiomorpholine (0.0096 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (5.1 mg, 0.012 mmol, yield 19%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 7 μl of acetic anhydride and 11 μl of pyridine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: [CH2:1]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:31])[C:15]3[C:20]([NH:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:17][C:16]=3[OH:30])=[O:9])[CH2:2]CCCC.[CH3:32][N:33](C)[CH2:34]CO>CCCCCC>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:1][O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[C:14](=[O:31])[C:15]3[C:20]([NH:21][C:22]=2[CH:23]=1)=[CH:19][C:18]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[CH:17][C:16]=3[OH:30])=[O:9]
Reactant: CCCCCCOC(=O)c1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3[nH]c2c1
Reactant: CN(C)CCO
Solvent: CCCCCC
Product: CN(C)CCOC(=O)c1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3[nH]c2c1
Yield: 27 %

Procedure:
8-Hydroxy-6-morpholin-4-yl-9-oxo-9,10-dihydro-acridine-3-carboxylic acid hexyl ester in. N,N-dimethylethanolamine (2 mL) was heated at 13.0° C. in sealed tube for 12 hours. Hexane (5 mL) was added, and a dark solid formed. The suspension was filtered and the remaining solid triturated with acetone. All residues were dissolved in MeOH and concentrated. The concentrate was purified via flash chromatography (CH2Cl2 to MeOH/CH2Cl2, 5:95) to yield an orange solid (10 mg, 27%). 1H NMR (CDCl3, 400 MHz) δ: 13.82 (s, 1H), 11.84 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.66 (d, 1H), 6.24 (s, 1H), 6.16 (s, 1H), 4.41 (t, 2H), 3.74-3.64 (m, 4H), 3.33-3.22 (m, 4H), 2.64 (t, 2H), 2.48 (s, 6H) LRMS (APCI, positive): Da/e 412.1 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Br:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:24][C:23]=1[Br:33]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Br:33])[C:22]([NH2:21])=[C:27]([Br:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: NCCNc1cc(Br)c(N)c(Br)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1cc(Br)c(N)c(Br)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-amino-3,5-dibromophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](O)(=[O:22])[CH2:18][C:19](O)=[O:20]>C(OC(=O)C)(=O)C>[C:11]1([N:10]2[C:19](=[O:20])[CH2:18][C:17](=[O:22])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(c2ccccc2)C(=O)N1c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
Acetic anhydride (290 ml) was added to 1,3-diphenylurea 18 (148 g), malonic acid 4 (81.6 g) was added under a nitrogen atmosphere, and the mixture was stirred at 90° C. for 3 hrs. The mixture was stirred at 100° C. for 1.5 hrs and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. Ethanol (500 ml) was added to the residue, and the mixture was stirred at 90° C. When the mixture was cooled to 40° C., the crystals were collected by filtration, washed with ethanol and dried to give 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g, yield 40%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH3:15].[Li]CCCC.CN([CH:24]=[O:25])C>>[CH3:13][N:12]([CH3:14])[C:7]1[CH:6]=[C:5]([CH3:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:24]=[O:25])[CH:3]=2)[N:8]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(N(C)C)nc2ccc(Br)cc12
Agent: [Li]CCCC
Product: Cc1cc(N(C)C)nc2ccc(C=O)cc12

Procedure:
To a stirred solution of 0.30 g (0.00113 moles) of 6-bromo-2-dimethylamino-4-methylquinoline in 30 ml of dry (freshly distilled from over LiAlH4) THF under N2 at -78° C., 1.45 ml (0.00226 moles) of 1.56M n-BuLi was added dropwise over a 5 minute period. 0.23 ml (0.00297 moles) of dry DMF (freshly distilled from over CaH2) was added to the reaction mixture in one portion. The dry ice/acetone bath was removed 12 minutes after the addition of DMF and the solution allowed to warm to -40°. The reaction mixture was poured onto 17 ml of 1N HCl in ice (22 minutes after addition of DMF) and extracted with 30 ml ether. The aqueous solution was made alkaline to pH 12 and extracted with three 20 ml portions of CH2Cl2. The yellow-orange coloured extract was washed with H2O and then dried over MgSO4 . The solvent was removed under vacuum, and the residue dried in a vacuum oven, wt 0.23 g (95.8%), m.p. 96°-99° C. The product was recrystallised three times (EtOH/H2O). The TLC of the recrystallised product showed several spots, with the predominant component having an Rf 0.38 in 2:1 hexane/EtOAc and being fluorescent under long hot UV. The product was dissolved in 2:1 hexane/EtOAc and placed on silica flash column. Fractions were collected; those containing the Rf 0.38 product were combined, and the solvent removed in vacuo. The residue was recrystallised from absolute ethanol; weight 0.04 g, (17%) m.p. 116.0°-117.8° C. Anal. Calcd. for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.74; H, 6.64; N, 13.05.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]#[N:18])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH2:20]([O:22][CH:23]=[CH2:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:1]([N:8]([CH2:16][C:17]#[N:18])[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@:10]1([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=COCC
Reactant: N#CCN(Cc1ccccc1)[C@@H]1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]
Solvent: C1CCOC1
Product: C=C(OCC)[C@@]1(O)CCCC[C@H]1N(CC#N)Cc1ccccc1
Temperature: 25 °C

Procedure:
To {benzyl[(1R)-2-oxocyclohexyl]amino}acetonitrile (298 mg, 1.230 mmol) in THF (9 ml) at −78° C. was added ethylvinyl ether lithium (7.38 ml, 3.69 mmol) in THF via a cannula dropwise over 25 min. The reaction mixture was stirred for an addition 40 min at −78° C. before wet THF (THF/Water 10/1, 10 ml) was added. The reaction was allowed to warm to room temperature. The mixture was cooled, aqueous potassium carbonate (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered and the solvent was evaporated under reduced pressure to give the title compound. The crude product was used directly without further purification in the next step.