Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:14]1([C@@H:2]([N:36]2[CH2:37][CH2:38][CH2:33][CH2:34][CH2:35]2)[C:3]([OH:5])=[O:4])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[OH:39][C:33]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:37][N:36]([C@H:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:35][CH2:34]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Product: O=C(O)[C@@H](c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF (25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) was added. The mixture was stirred for 16 hours and then it was diluted with ethyl acetate (100 mL), washed (H2O×2, brine), dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (0-60% ethyl acetate-hexane) to provide an approximately 2:1 mixture of diastereomers, as judged by 1H NMR. Separation of these isomers was performed using supercritical fluid chromatography (CHIRALCEL® OJ-H, 30×250 mm; 20% ethanol in CO2 at 35° C.), to give first the (R)-isomer of the title compound (0.534 g, 27%) as a yellow oil and then the corresponding (S)-isomer (0.271 g, 14%), also as a yellow oil. (S,R)-isomer: 1H NMR (400 MHz, CD3OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt, J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1, 4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LC-MS: Anal. Calcd. for C27H29NO3: 415. found: 416 (M+H)+; (S,S)-isomer: H1NMR (400 MHz, CD3OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m, 1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12 (dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd, J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LC-MS: Anal. Calcd. for C27H29NO3: 415. found: 416 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)#[CH:37]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:37]#[C:36][C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C#Cc4ccc(F)cc4)cn3)c2CC1
Temperature: 65 °C
Yield: 94.2 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 2.07 mmol), tetrakistriphenylphosphine palladium(0) (120 mg, 0.104 mmol), cuprous iodide-(20 mg, 0.105 mmol), triethylamine (2.60 mL) and 1-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). Degas the mixture, purge with nitrogen, and heat at 65° C. for 3 days. Dilute the mixture with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (50:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a tan foam (1.02 g, 95%). MS (APCI+) m/z: 523 (M+H)+, 423 (M+H−Boc)+. Use a method similar to the General Procedure 14 to give the title compound as a tan powder. MS (APCI+) m/z: 423 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH:4]([C:3]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:2]=1[C:21]1[C:16]([O:15][CH3:14])=[CH:17][CH:18]=[C:19]([CH2:22][C:23]#[N:24])[CH:20]=1)=[O:5]
Reactant: COc1ccc(CC#N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: COc1ccc(CC#N)cc1-c1ccc(C(F)(F)F)cc1C=O

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C)C=O>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
DIEA (0.046 mL, 0.27 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.050 g, 0.24 mmol) and HATU (0.101 g, 0.27 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.051 g, 0.24 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.021 g of 1541A in a 22% yield: LCMS (ESI) m/z 398 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH2:16][C:17]1[C:25]2[C:20](=C[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=3[F:33])[CH:24]=2)[NH:19][N:18]=1.[N:34]1C=CC=CC=1>>[CH2:1]([N:3]([CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:34][C:20]2[C:25]3[C:17](=[N:16][N:22]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=4[F:33])[CH:24]=3)[NH:18][N:19]=2)=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: c1ccncc1
Reactant: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12
Reactant: CCN(CC)Cc1ccc(C(=O)Cl)cc1
Product: CCN(CC)Cc1ccc(C(=O)Nc2n[nH]c3nnc(-c4cccc(F)c4F)cc23)cc1

Procedure:
4-Diethylaminomethylbenzoyl chloride (0.503 g, 2.43 mmol) was added to a solution of 3-amino-5-(2,3-difluorophenyl)-1H-pyrazolo[3,4-c]pyridine (Description 14; 0.200 g, 0.81 mmol) in pyridine (5 mL). The mixture was heated at reflux for 16 hours then the solvent was removed under reduced pressure. The residue was azeotroped, firstly with water and then with ethanol. The resulting solid was dissolved in dimethylformamide and purified initially by preparative HPLC on a C18 column, using a gradient elution with 10-90% v/v of acetonitrile (containing 0.01% trifluoroacetic acid) and water (containing 0.1% trifluoroacetic acid). Subsequent purification by silica gel chromatography using initially 5% v/v methanol in dichloromethane as eluent, followed by 5% v/v 1N methanolic ammonia in dichloromethane as eluent afforded the title compound, a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH2:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl.O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][NH:17][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CN)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CNC(=O)c2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.4 %

Procedure:
2-{[4-(Aminomethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 13 and 4-bromobenzoic acid (2.51 g) was dissolved in dichloromethane (50 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (2.99 g) and hydroxybenzotriazole (HOBT) monohydrate (2.39 g) were successively added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (3.5 g) as a white solid.
Reaction SMILES: [Cl:1][CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Cl:1][CH:2]([C:13]#[N:14])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:17])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: N#CC(Cl)Cc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Product: N#CC(Cl)Cc1ccccc1C(=O)Cl

Procedure:
209.5 parts of 2-(2-chloro-2-cyanoethyl) benzoic acid are made into a paste in 220 parts of toluene and 125 parts of thionyl chloride and the mixture is refluxed until the acid completely dissolves. Then the surplus thionyl chloride and toluene are eliminated under reduced pressure. 2-(2-chloro-2-cyanoethyl) benzoyl chloride is obtained which is liquid at normal temperature.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:29][C:30]1[CH:35]=[C:34]([O:36][C:37]2[C:42]([F:43])=[CH:41][C:40]([NH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=4)=[O:51])[CH2:49][CH2:48]3)=[O:46])=[C:39]([F:60])[CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of (R)-2-benzyloxy-propionic acid (500 mg, 2.78 mmol) and N-methylmorpholine (416 mg, 4.16 mmol) in anhydrous CH2Cl2 was added isobutyl chloroformate (566 mg, 4.32 mmol) dropwise. The mixture was stirred at 25° C. for 1 h. N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated in vacuo to give (R)—N-(4-((2-(2-(benzyloxy)propanamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 71.5%). It was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[O:20]C)[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1
Reactant: COc1cccc(C)c1-c1nc(Cl)c2ccc(C)cc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(Cl)nc(-c3c(C)cccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-2-(2-methoxy-6-methylphenyl)-7-methylquinazoline (669 mg, 2.24 mmol) in 7 mL CH2Cl2 was added dropwise 5 equivalents of a 1 M solution of BBr3 in CH2Cl2 at −78° C. The reaction was warmed to room temperature and was complete in 30 minutes. The reaction was quenched with a saturated aqueous NaHCO3 solution until the pH was neutral. The aqueous layer was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated to obtain 2-(4-chloro-7-methylquinazolin-2-yl)-3-methylphenol. LC/MS: m/z 285.1 (M+H)+ at 3.94 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37](Cl)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1>C1COCC1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:32]1[C:36]([C:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:38])=[C:35]([CH3:40])[O:34][N:33]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 571.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=[S:12])=[N:6][N:5]=[N:4]1>O>[CH3:2][N:3]1[C:7]([CH:8]([CH3:15])[CH2:9][CH2:10][C:11]([OH:13])=[S:12])=[N:6][N:5]=[N:4]1
Reactant: COC(=S)CCC(C)c1nnnn1C
Agent: Cl
Solvent: O
Product: CC(CCC(O)=S)c1nnnn1C

Procedure:
20% aqueous Hydrochloric acid (150 ml) is added to methyl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valerate (17 g) and the mixture is refluxed for 2 hours. After cooling, the reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to give 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-valeric acid, colorless liquid, nD26 =1.5133.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]=[C:11]([S:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1>N1C=CC=CC=1>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]=[C:11]([S:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:3]([NH:2][CH3:1])=[O:4])=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1
Reactant: CN=C=O
Reactant: Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Solvent: c1ccncc1
Product: CNC(=O)Nc1ccc(Sc2nc3ccc(Cl)cc3s2)cc1
Yield: 62.8 %

Procedure:
Methyl isocyanate (0.41 g) was added to a solution of 4-(6-chlorobenzothiazol-2-ylthio)-aniline (2.0 g) in pyridine (20 ml), with stirring. The mixture was stirred at room temperature for 12 hours and evaporated to dryness. The residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give N-[4-(6-chlorobenzothiazol-2-ylthio)phenyl]-N'-methylurea (1.5 g), which had a melting point of 289°-291° C. This urea (1.4 g) was dissolved in 1,4-dioxane (50 ml), and chlorocarbonyl isocyanate (0.47 g) was added. The mixture was heated at the boiling point for 5 hours and evaporated to dryness. The solid residue was dissolved in a minimal volume of boiling ethanol and the solution was cooled in a refrigerator. The resulting solid substance was collected by filtration and dried to give 1.3 g of 1-[4-(6-chlorobenzothiazol-2-y(thio)phenyl]-3-methyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione of melting point 232°-233° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:22]([OH:24])=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30](=[O:46])[NH:31][CH2:32][CH2:33][CH2:34][C@H:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][NH2:37])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:15]([O:14][C:12](=[O:13])[NH:11][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:22]([NH:37][CH2:36][C@@H:35]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:46])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 150 mg (0.46 mmol) of O-benzyl-N-[(benzyloxy)carbonyl]-L-serine and 188 mg (0.59 mmol) of tert-butyl{(4S)-5-amino-4-[(tert-butoxycarbonyl)amino]pentyl}carbamate (Example 86A) in 6 ml of dimethylformamide with the addition of 114 mg (0.57 mmol) of EDC and 18 mg (0.13 mmol) of HOBt. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→5:95).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=5[CH3:35])[NH2:31])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:12][CH:11]=1.[CH3:38][C:39]1[N:40]([C:44]2[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=2)[C:47](O)=[O:48])[CH:41]=[CH:42][N:43]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]3[CH:21]=[C:22]4[N:27]([C:28]5[CH:29]=[C:30]([NH:31][C:47](=[O:48])[C:46]6[CH:50]=[C:51]([C:53]([F:54])([F:55])[F:56])[CH:52]=[C:44]([N:40]7[CH:41]=[CH:42][N:43]=[C:39]7[CH3:38])[CH:45]=6)[CH:32]=[CH:33][C:34]=5[CH3:35])[CH:26]=[CH:25][N:23]4[N:24]=3)[CH:17]=[N:16]2)=[CH:36][CH:37]=1
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(-n7ccnc7C)cc(C(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1

Procedure:
60 mg (0.12 mmol) of the compound of Example 8A and 31.6 mg (0.12 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281-A1, Example 91b] were reacted and worked up analogously to the procedure of Example 48A. This gave 61 mg (77% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCCCCc1oc(-c2ccc(Cl)cc2)nc1CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCc1oc(-c2ccc(Cl)cc2)nc1CC(=O)O
Yield: 87.3 %

Procedure:
1.0 g of ethyl 2-[2-(4-chlorophenyl)-5-n-pentyl-4-oxazolyl]acetate, 10 ml of methanol, 3 ml of water and 0.4 g of potassium hydroxide are treated in the same manner as described in Example 8. 0.8 g of 2-[2-(4-chlorophenyl)-5-n-pentyl-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.2%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:10]([NH:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600 mL of CH2Cl2 was added 2.0 eq. of phenethylamine (Aldrich) dropwise. The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory and extracted with CH2Cl2. The organic extracts were washed with water and 1N HCl, and then dried over Na2SO4, filtered and concentrated to give N-phenethyl benzamide.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27]1)=[O:34])[CH3:37]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Reactant: CCOC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)C1

Procedure:
The same procedure as described in Example 54 was used, starting with [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 53, and ethyl chloroformate (Aldrich) to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester. MS (M+H)+, 400.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)CCC.O.CCOC(C)=O>O1CCOCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 25.2 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (225 mg, 0.460 mmol) in dioxane (3 mL) was degassed with Ar before being charged with 4-tributylstannylpyridine (371 mg, 1.01 mmol) and Pd(Ph3P)4 (98 mg, 0.085 mmol). The mixture was stirred at 100° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (51 mg).