Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[C:6]=2[N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24]>>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][CH:22]=[C:11]([C:8]3[C:6]4[N:7]=[C:2]([NH:37][C:34]5[CH:35]=[N:36][C:31]([N:28]6[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]6)=[CH:32][CH:33]=5)[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(NC1CC1)c1cccc(-c2csc3cnc(Cl)nc23)c1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cccc(C(=O)NC6CC6)c5)c4n3)cn2)CC1
Yield: 51.1 %

Procedure:
N-Cyclopropyl-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide (23 mg, 50% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)-N-cyclopropylbenzamide (30 mg, 0.09 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (28 mg, 0.14 mmol).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(F)(F)F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-trifluoromethylphenyl isocyanate (0.169 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 148 mg (42.1%) of the desired product as a solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Br.[C:7]([C:15]1[N:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][N:20]([N:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: O=C(Br)CBr
Reactant: CNn1cccc1C(=O)c1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)CBr)n1cccc1C(=O)c1ccccc1
Yield: 81.5 %

Procedure:
A solution of bromoacetyl bromide (8.47 g, 42 mmol) in 30 ml of dichloromethane was added over 30 minutes to a stirred slurry containing 2-benzoyl-1-methylaminopyrrole hydrobromide (14.9 g, 54.7 mmol) and sodium bicarbonate (5.9 g, 71 mmol) in 150 ml of dichloromethane. After 22 hours at room temperature the mixture was quenched with 150 ml of crushed ice and the layers were separated. The organic layer was washed with water, dried over anhydrous MgSO4, filtered and evaporated. The residual oil was flash chromatographed (silica gel, 5% hexane-ethyl acetate) to give 11.0 g (98%) of crystals, m.p. 76°-78°. A 2.2 g portion of this material was recrystallized from ether-hexane to afford 2.1 g of cubes, m.p. 76°-78°.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=O.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[N:13][OH:14]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCC(C)CC=NO

Procedure:
3,7-Dimethyloct-6-enal (15.4 g) in 50 ml ethyl alchohol was added to a solution of hydroxylamine hydrochloride (7 g) and sodium carbonate (5 g) in 25 ml of water. The mixture was heated on the steambath for 15 minutes and then allowed to cool. Addition of an excess of water yielded 3,7-dimethyloct-6-enal oxime as an oil. The oil was extracted with ether and the organic layer dried and evaporated. The residue was added dropwise to a solution of lithium aluminum hydride (3.8 g) in 380 ml anhydrous ethyl ether. After refluxing overnight an additional quantity of lithium aluminum hydride (0.78 g) was added to complete the reduction. Decomposition of the reaction mixture with excess aqueous sodium hydroxide (200 ml of 10% solution), separation of the ether layer, and distillation yielded 3,7-dimethyloct-6-enyl amine (10 g) bp 60°/0.5 mm). To an ice cold solution of this amine (1.5 g) and triethylamine (1.1 g) in ether (25 ml) was added dropwise a solution of ethyl chloroformate (1.1 g) in ether (10 ml). The reaction mixture was allowed to stand overnight at room temperature. The triethylamine hydrochloride was filtered off and the ether solution washed with water, dilute hydrochloric acid, and again with water. The ether solution was dried and evaporated and the residue distilled to yield 2 g carbamic acid (3,7-dimethyl-6-octenyl)-, ethyl ester (Compound 7), bp 102°-103°/0.1 mm. The ester was epoxidized as described in the previous examples to yield VII. The crude reaction product can be readily purified by chromatography using neutral activated alumina.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][CH:8]([F:28])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>C(#N)C.O>[F:28][CH:8]([F:7])[O:9][C:10]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][C:11]=1[C:12]([NH:14][CH3:1])=[O:13]
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(C(N)=O)c2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of the appropriate chloro-substrate (1 equiv), potassium carbonate (3.0 equiv), 2-difluoromethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (1.1 equiv) and tetrakis(triphenylphosphine) palladium0 (0.05 equiv) in acetonitrile/water (0.1 M of chloro-substrate) was stirred at 100° C. for 2 hours. Upon completion the reaction mixture was partitioned between water and CH2Cl2 and extracted with CH2Cl2. Combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: Cl[C:2]1[C:13]([C:14](=O)[C:15]2SC=CC=2)=[CH:12][C:5]2CC(C(O)=O)O[C:4]=2[C:3]=1Cl.C(#[N:24])C>>[CH3:15][CH:14]([NH2:24])[C:13]1[CH:12]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: CC#N
Product: CC(N)c1ccccc1

Procedure:
By following substantially the procedure described in step A, the partially resolved 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylic acid (12.0 g., 0.035 mole); (obtained from the acetonitrile mother liquor of step A) and (+)-α-methylbenzylamine (4.3 g., 0.035 mole) are mixed in acetonitrile (1000 ml.). The resultant salt (14.5 g.) was thrice recrystallized from a minimum volume of acetonitrile and ethanol (10:1) to obtain 9.4 g. of the salt of the pure (-)-enantiomer which is converted to the acid by treatment of the salt with dilute hydrochloric acid and ether.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH:10]1[CH:11]=[CH:12][C:13]2[NH:18][CH:17]=[C:16]([CH2:19][CH2:20][OH:21])[C:14]=2[CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:17]2[NH:18][C:13]3[C:14]([C:16]=2[CH2:19][CH2:20][O:21]1)=[CH:15][CH:10]=[CH:11][CH:12]=3)[CH3:9]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 2 1/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b-]indole-1-acetic acid ethyl ester, as an oil, γ maxCHCl3 1715 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:17]([NH2:18])=[N:16][C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[CH:8]=2)[CH:2]=1.[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[C:17]([NH:18][C:24]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:16][C:10]=2[N:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ncc2cc(-c3cccnc3)c(N)nc2n1
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1cccnc1

Procedure:
By following the procedure of Example 2, 0.30 g of 2,7-diamino-6-(3-pyridyl)-pyrido[2,3-d]pyrido[2,3-d]-pyrimidine from Example 107 was reacted with 0.16 mL of tert-butyl isocyanate. The product was purified by medium pressure chromatography using silica gel and eluting with 90:10:1 EtOAc:MeOH:TEA to afford the title compound; mp >300° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 338 (MH+ +1, 8), 339 (MH+ +2, 1), 84 (100).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:56](OC)[CH3:57])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:60]O[C@H](C)[C@H](NC(OC)=O)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:56]([CH3:57])[CH3:60])[C:7]([N:9]1[C@H:14]([C:15]2[NH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[CH:27]=[C:28]5[C:52](=[CH:53][CH:54]=4)[C:32]4[NH:33][C:34]([C@@H:36]6[CH2:40][CH2:39][CH2:38][N:37]6[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:44])[CH3:45])=[N:35][C:31]=4[CH:30]=[CH:29]5)=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[C@@H:13]2[CH2:55][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)ccc3c2[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc(-c5cnc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(7-(4-(2-((1R,3S,4S)-2-((2S,3R)-2-methoxycarbonylamino-3-methoxybutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid for (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid. (ESI) m/z 789 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[C:11](=[O:17])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[C:11](=[O:17])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN1CCN(c2ccc(N)cc2F)CC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
5-Amino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (2.95 g) was dissolved in dry dichloromethane (50 ml) under argon. Pyridine (1.26 ml) was added, and the mixture cooled to -20° C. Benzyl chloroformate (1.95 ml) was added, and the mixture stirred for 10 minutes at -20° C., before allowing the temperature to rise to ambient over 1.5 hours. Solvents were evaporated, the residue dissolved in dichloromethane and washed with sodium bicarbonate solution. After drying (MgSO4) and evaporation of solvent, the residue was chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 5-benzyloxycarbonylamino-2-(4-ethyl-3-oxopiperazin-1-yl)fluorobenzene (3.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]=[C:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=4[NH:8][C:9]=3[CH:10]=2)[CH2:27][CH2:26]1
Reactant: CN1CCN(CCO)CC1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Product: CN1CCN(CCOc2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4ccccc4)nc23)CC1

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and 2-(4-methylpiperazin-1-yl)ethanol. MS (ESI) m/z 430.1 (M+H). 1H NMR (400 MHz, MeOD) δ ppm 8.20-8.27 (1H, m), 8.12 (1H, s), 8.04-8.09 (2H, m), 7.46-7.53 (2H, m), 7.37-7.42 (1H, m), 7.12-7.16 (1H, m), 6.87-6.94 (1H, m), 4.18-4.27 (2H, m), 2.87 (2H, t, J=5.41 Hz), 2.42-2.77 (6H, m), 2.27 (3H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:23])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].CCN(CC)CC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[CH2:24]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:34](=[O:35])[O:36][CH2:37][CH3:38])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:25]
Reactant: CCN(CC)c1ccc(NC(=O)C2(N)CCc3ccccc3C2)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC1(C(=O)Nc2ccc(N(CC)CC)cc2)CCc2ccccc2C1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
The amine from Example 8A (34 mg, 0.1 mmol) was dissolved in THF (0.5 mL) and Et3N (15 mg, 0.1 mmol) and ethyl chloroformate (13 mg, 0.12 mmol) were added at 0° C. after which the mixture was allowed to stir overnight. HPLC purification gave the titled compound (10 mg, 24%). 1H NMR (300 MHz, DMSO-D6) δ 9.14 (s, 1H), 7.32 (d, J=8.7 Hz, 2H), 7.08 (m, 4H), 7.08 (s, 1H), 6.61 (d, J=9.0 Hz, 2H), 3.96 (m, 2H), 3.28 (q, J=6.6 Hz, 4H), 3.02 (d, J=16.5 Hz, 1H), 2.73 (m, 2H), 2.36 (m, 1H), 2.05 (m, 1H), 1.13 (t, J=6.9 Hz, 3H), and 1.05 (t, J=7.2 Hz, 6H). (one proton (ArCHnHbC(C═O)) overlapped with water)). MS (ESI) positive ion 410 (M+H)+; negative ion 408 (M−H)−.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:49]1([S:52](Cl)(=[O:54])=[O:53])[CH2:51][CH2:50]1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:52]([CH:49]1[CH2:51][CH2:50]1)(=[O:54])=[O:53])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C3CC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 75 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added cyclopropanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH2:9][CH2:10][CH:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N:13]2[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[OH:32])[C:14]2=[O:15])=[CH:17][CH:18]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Temperature: 60 °C

Procedure:
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) were dissolved in 90 ml of ethanol. 10 ml of conc. ammonia solution and an excess of Raney nickel were added, and the mixture was stirred at 60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cooled to room temperature. The next day, the catalyst was removed, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane/methanol/ammonia solution 10/1/0.1. This produced 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH+-NH3).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+].CN(C=O)C>O>[C:24]([O:27][C:2]1[C:7]([C:8](=[O:9])[NH2:10])=[C:6]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1)(=[O:26])[CH3:25]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2cnc3ccccc3c2)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(Nc2cnc3ccccc3c2)c(C(N)=O)c(OC(C)=O)n1
Temperature: 100 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
To a mixture of 4-chloro-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide (Preparation Example 344) (0.68 g) and sodium acetate (0.80 g), DMF (7 mL) was added and stirred at 100° C. for 6 hours. After the reaction liquid was returned to room temperature, water was added, and the resulting solid was collected by filtration to give 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-yl acetate (0.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:28])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[N:26]=[C:25]([CH3:27])[O:24][N:23]=1)[CH3:28]
Reactant: Cc1nc(C(C)(C)N)no1
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: COc1ccc(C(=O)NC(C)(C)c2noc(C)n2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81 c) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=387.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.[CH3:16]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Agent: Cl
Product: COC(=O)c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Commercially available 4-methyl-1-naphthalenecarboxylic acid (250.6 mg) was dissolved in methanol (7.5 ml). Hydrogen chloride gas was blown into the solution for five minutes while cooling with ice. Then, the mixture was stirred for 19 hours at room temperature and the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was dried under reduced pressure to obtain the target compound (269.9 mg) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:39])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCN3C(=O)c4ccccc4C3=O)cc2)cn1

Procedure:
To a solution of the compound obtained from step e above (0.6 g) in methanol (10 mL), 10% palladium on charcoal (0.05 g) was added at room temperature and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (0.56 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9](=[O:26])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]([OH:26])[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1OC
Reactant: [H][H]
Solvent: CCO
Product: COc1ccc(C2COc3c(ccc(OC(C)=O)c3C)C2O)cc1OC

Procedure:
In a 1 L 3N round-bottomed hydrogenation flask, 7-acetoxy-3-(3,4-dimethoxyphenyl)-8-methylchromen-4-one (13.9 g) and Pd/Al2O3 (2.8 g) were suspended in absolute ethanol (560 mL). Hydrogen was introduced to the system for 42 h until the reaction was complete. The reaction mixture was separated by filtration with Celite. The solvent was removed in vacuo to give a white solid which was dried overnight on a high-vacuum line yielding 7-acetoxy3-(3,4-dimethoxyphenyl)-8-methylchroman-4-ol as a mixture of cis- and trans-isomers (9.56 g, 68%). This mixture was used in the next step without any further purification.