Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[N:26]=[CH:25][CH:24]=CN=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:35]1N=CC=C[N:36]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:35]=[N:36][CH:24]=[CH:25][N:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc2cc(-c3ncccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Brc1ncccn1
Product: Cc1cc2cc(-c3cnccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrazin-2-yl)naphthalen-2-yl)acetic acid was prepared in a similar fashion to compound 59 with the substitution of 2-chloropyrazine for 2-bromopyrimidine in step 2. The title compound (0.026 g) was isolated as an amorphous pale yellow powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O3: 461.96; found: 461.30. 1H-NMR: 400 MHz, (CD3CN) δ: 9.23 (s, 1H); 8.67 (s, 1H); 8.56 (s, 2H); 8.05 (d, J=8.8 Hz, 1H); 7.89 (s, 1H); 7.61-7.54 (m, 3H); 7.42 (d, J=8.8 Hz, 1H); 7.39 (br d, J=8.8 Hz, 1H); 5.23 (s, 1H); 2.60 (s, 3H); 1.00 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[S:23]([NH:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:5]=2[N:6]=1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Reactant: CC1(C)CC(=O)c2sc(N)nc2C1
Product: CC1(C)CC(=O)c2sc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3Cl)nc2C1

Procedure:
The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (47.2 mg) with purity >90%: MS (pos) m/z 439.3, 441.3; HRMS m/z 437.9451 (calc. of monoisotopic mass for C15H13Cl3N2O3S2 gives 437.9433).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([C:18]1[N:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:21][C:22]=1[CH2:23][OH:24])[CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:14]([C:18]1[N:19]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=2)[S:21][C:22]=1[CH2:23][O:24][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of 100 mg of 4-fluoro-2-trifluoromethyl benzonitrile in 5 ml of anhydrous dimethylformamide was added 200 mg of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol and 0.49 g of cesium carbonate. The resulting mixture was stirred at room temperature overnight, poured onto water and extracted with heptane 1/ethyl acetate 3. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 4/ethyl acetate 1) to give 180 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-trifluoromethyl-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7].S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(Br)o1
Temperature: 50 °C
Reaction time: 96 h
Yield: 92 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (5.7 g, 21.1 mmol) in methanol (106 ml) was added sulfuric acid (11.3 ml, 211 mmol). The resulting solution stirred at 50° C. over 4 days. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (5.5 g, 19.4 mmol, 92% yield): LCMS (ES) m/e 283 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].[NH2:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:34]=[C:33]([CH2:35][CH3:36])[C:23]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[OH:37]>C(OCC)C.[OH-].[Na+]>[C:25]([NH:24][C:23]1[C:33]([CH2:35][CH3:36])=[CH:34][N:19]([C@@H:17]2[O:18][C@H:14]([CH2:13][NH:12][C:9](=[O:10])[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[C@@H:15]([OH:37])[CH2:16]2)[C:20](=[O:21])[N:22]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)nc1NC(=O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3Br)O2)c(=O)nc1NC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
A solution of 210 mg of (2-bromophenyl)acetyl chloride in 3 ml of diethyl ether was added to a solution of 324 mg of 5'-amino-4-N-benzoyl-2',5'-dideoxy-5-ethylcytidine in 4.9 ml of 0.18M sodium hydroxide solution and the mixture was shaken vigorously for 10 minutes. The solid was collected by filtration, washed with 2 ml of water and 1 ml of diethyl ether and recrystallized from 15 ml of ethanol to give 100 mg of 4-N-benzoyl-5'-[2-(2-bromophenyl)acetamido]-2',5'-dideoxy-5-ethylcytidine in the form of a white solid which was processed further without purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)[C:6]=1[C:25]([OH:27])=[O:26])(O)=[O:2].FC1C=CC2SC=C([CH2:36][N:37]3C4C(=CC=CC=4)C4CC(=O)OC(=O)[C:38]3=4)C=2C=1.CNC>>[CH3:36][N:37]([CH3:38])[C:1]([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[C:16]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=3[S:18][CH:19]=2)[C:6]=1[C:25]([OH:27])=[O:26])=[O:2]
Reactant: O=C(O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12
Reactant: O=C1Cc2c(n(Cc3csc4ccc(F)cc34)c3ccccc23)C(=O)O1
Agent: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2csc3ccc(F)cc23)c2ccccc12

Procedure:
3-Carboxymethyl-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid (from Example 59) was converted to 9-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione as described in Example 68.1. which was converted according to Example 68.2. but using dimethyl amine to give 3-dimethylcarbamoylmethyl-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 409.4 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14](I)[N:15]=[C:5]3[C:4]=2[CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.C[N:27](C)[CH:28]=[O:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:28]([NH2:27])=[O:29])[N:15]=[C:5]3[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)OCCn1cc(I)nc1-2
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Temperature: 70 °C

Procedure:
A mixture of 10-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (2056 mg, 5.916 mmol), bis(triphenylphosphine)palladium(II) chloride (2.10E2 mg, 0.300 mmol) and hexamethyldisilazane (7.488 mL, 35.50 mmol) in 60 ml of N,N-Dimethylformamide was subjected to carbonylation at 1 atm with CO from balloon. The reaction mixture was heated at 70° C. for 1 h. The mixture was concentrated in vacuum, the residue partitioned between ethyl acetate and 1 M aqueous sodium carbonate. The organic extracts were washed with water, brine, dried over magnesium sulfate, concentrated in vacuum and purified on a 12 g silica column eluting with 0-5% MeOH in DCM to give 1300 mg (83%). MS (ESI+): 265.0. 1H NMR (500 MHz, DMSO) δ 8.37 (s, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.70 (s, 1H), 7.25 (s, 1H), 4.56 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Cl)cc2c(Cl)n[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 4-((1-(3,5-dichloro-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (4.6 g, 8.80 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 40 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a 20 g phenomenex strata giga tube strong cation exchange cartridge. After flushing the cartridge with several volumes of methanol (which were discarded), the product was eluted with 2M ammonia in methanol to give 3.75 g (100%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 9.88 (bs, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.26 (dd, J=8.9, 5.5 Hz, 2H), 7.06 (dd, J=8.5, 8.5 Hz, 2H), 7.01 (d, J=1.1 Hz, 1H), 4.49 (q, J=6.4 Hz, 1H), 3.41 (d, J=8.9 Hz, 1H), 3.27 (d, J=8.9 Hz, 1H), 2.91 (m, 2H), 2.73 (m, 2H), 2.20 (m, 1H), 2.05 (m, 1H), 1.87 (m, 2H), 1.42 (d, J=6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.4 (d, J=246 Hz), 139.0, 136.9, 134.1, 128.5 (d, J=7.8 Hz), 128.3, 126.8, 125.2, 121.9, 117.7, 115.5 (d, J=21 Hz), 79.0, 77.9, 42.4, 42.3, 41.2, 33.5, 33.2, 22.0. Mass spec.: 328.12 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[C:10]=[S:11]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:10](=[S:11])[NH:9][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: Nc1ccc(N)cc1
Solvent: CC#N
Product: Nc1ccc(NC(=S)Nc2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,4-diaminobenzene (0.324 g, 3.0 mmol) in acetonitrile was added 4-isothiocyanatobenzenesulfonamide (0.642 g, 3.0 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture went clear and a white precipitate formed. The solid was filtered, washed with acetonitrile and dried to afford 4-(3-(4-aminophenyl)thioureido)-benzenesulfonamide as a white sold (0.829 g, 86%). 1H NMR (400 MHz, DMSO) δ 9.65 (s, 2H), 7.71 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.26 (s, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.52 (d, J=6.8 Hz, 2H), 5.08 (s, 2H); MS (ESI), 323 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([O:17]C)[CH:3]=1.C[S-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1C(=O)c1ccccc1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)c(C(=O)c2ccccc2)cc1C
Temperature: 25 °C

Procedure:
(4,5-Dimethyl-2-methoxyphenyl)(phenyl)methanone (650 mg) was dissolved in dimethylformamide (10 ml) to prepare a solution. Sodium thiomethoxide (379 mg) was added to the solution, and the mixture was stirred while heating under reflux overnight. The reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate and was concentrated. The residue was subjected to separation and purification by column chromatography on silica gel using hexane/ethyl acetate as a solvent to give (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone. The (4,5-dimethyl-2-hydroxy-phenyl)(phenyl)methanone (40 mg) thus obtained and 4-chloro-6,7-dimethoxyquinoline (150 mg) were added to o-dichlorobenzene (0.2 ml), and the mixture was heated at 180° C. for two days. The reaction solution was concentrated and was subjected to separation and purification by column chromatography on silica gel using hexane-ethyl acetate. Subsequently, a hydrochloric acid-methanol mixed solution was added thereto, the solvent was removed by distillation, and the residue was suspended in ethyl acetate. The solid thus obtained was collected by filtration, was washed with ethyl acetate, and was then dried to give the title compound (9.2 mg, yield 11%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=O)[CH:14]([CH3:25])[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=O)=[CH:7][CH:6]=1>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:2]([CH3:1])[N:3]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:14]=2[CH3:25])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: CC(C(=O)CCc1ccc(F)cc1)C(=O)c1cccc(C#N)c1
Solvent: CCO
Product: Cc1c(-c2cccc(C#N)c2)nn(C)c1CCc1ccc(F)cc1
Yield: 32.7 %

Procedure:
EtOH (20 mL) and methyl hydrazine (162 μL, 3.05 mmol) were added to the product of Step 1 (630 mg, 2.04 mmol) and the mixture heated at reflux for 90 min. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica eluting with 40% EtOAc/iso-hexanes to yield first 3-{5-[2-(4-fluorophenyl)-ethyl]-1,4-dimethyl-1H-pyrazol-3-yl}-benzonitrile (213 mg, 33%) (byproduct) and then the desired 3-{3-[2-(4-fluorophenyl)-ethyl]-1,4-dimethyl-1H-pyrazol-5-yl}-benzonitrile (250 mg, 38%).
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:8][CH2:9][P:10]([CH2:15][N:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:36](Br)[CH:37]=[CH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:24]1([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][CH:15]([P:10]([CH:9]([N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:31][CH:30]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:14])[O:11][CH2:12][CH3:13])[CH2:36][CH:37]=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Product: CCOP(=O)(C(CC=Cc1ccccc1)N=C(c1ccccc1)c1ccccc1)C(CC=Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Yield: 76 %

Procedure:
Analogously to example 6, the bis-alkylated phosphinates 8 were prepared in a yield of 76% from the protected phosphinate 3 and cinnamyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35](=[O:40])[CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][C:35](=[O:40])[CH2:34]5)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc2c(c1)CC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4ccc5c(c4)CC(=O)N5)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.9 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (100 mg, 0.24 mmol) and 5-aminoindolin-2-one (36 mg, 0.24 mmol) in dichloromethane (20 mL) were added 1-methyl-1H-imidazole (79 mg, 0.96 mmol) and EDCI (183 mg, 0.96 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid was collected by filtration and washed with methanol (4 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-oxoindolin-5-yl)piperidine-3-carboxamide as a orange solid (68 mg, 51.8%). 1H NMR (300 MHz, DMSO): δ 10.31 (s, 1H), 9.87 (s, 1H), 9.67 (s, 1H), 8.86 (s, 1H), 7.68 (d, 1H, J=2.4 Hz), 7.53 (s, 1H), 7.37 (s, 1H), 7.35 (s, 1H), 6.83-6.81 (m, 1H), 6.75 (d, 1H, J=8.4 Hz), 4.82-4.67 (m, 2H), 3.71-3.65 (m, 6H), 3.48 (s, 2H), 3.12-2.95 (m, 2H), 1.98-1.74 (m, 5H). LC-MS: 546 [M+H]+, tR=1.493 min. HPLC: 98.74% at 214 nm, 98.67% at 25 4 nm, tR=3.60 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23](N)[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[Cl-:28].[Cs+]>Cl[Cu]>[Cl:28][C:23]1[S:24][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=4)[N:14]=[CH:13][N:12]=3)[C:21]=2[N:22]=1
Reactant: [Cl-]
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Agent: Cl[Cu]
Agent: [Cs+]
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sc(Cl)nc34)ncn2)cc1

Procedure:
The title compound was prepared in an analogous manner to the conditions of Example 91 by reacting 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine (Example 65) with CsCl and CuCl. MS (ESI, pos. ion.) m/z: 408 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([O:28][Si](C(C)(C)C)(C)C)[CH2:24]2)[C:20](=[O:36])[NH:19][C:18]2([C:37]([NH:39][S:40]([CH:43]3[CH2:45][CH2:44]3)(=[O:42])=[O:41])=[O:38])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6](=[O:46])[NH:7][CH:8]1[C:26](=[O:27])[N:25]2[CH:21]([CH2:22][CH:23]([OH:28])[CH2:24]2)[C:20](=[O:36])[NH:19][C:18]2([C:37]([NH:39][S:40]([CH:43]3[CH2:45][CH2:44]3)(=[O:41])=[O:42])=[O:38])[CH:16]([CH2:17]2)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.8 %

Procedure:
To a mixture of [18-(tert-butyl-dimethylsilanyloxy)-4-cyclopropanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester (330 mg, 0.48 mmoL) in 25 mL of THF was added tetrabutylammonium floride (150 mg, 0.54 mmoL). The reaction mixture was stirred at rt for 18 h, and then the THF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. It was then purified by triturating with hexane to yield 200 mg (73%) of (4-cyclopropanesulfonylaminocarbonyl-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (500 MHz, CD3Cl) δ 1.87–1.64 (m, 21H), 1.70–1.98 (m, 3H), 2.15–2.56 (m, 5H), 2.85–2.94 (m, 1H), 3.71 (d, J=13.91 Hz, 1H), 4.10–4.26 (m, 2H), 4.51 (t, J=7.87 Hz, 1H), 4.62 (s, 1H), 4.98 (m, 1H), 5.06 (d, J=8.78 Hz, 1H), 5.64–5.71 (m, 1H), 6.72 (s, 1H), 10.24 (s, 1H). LC-MS (Method A, retention time: 2.85 min), MS m/z 569 (M++1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:19](=[O:20])[NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH2:2]2
Reactant: COc1cccc(N=C=O)c1
Reactant: OC1CN2CCC1CC2
Product: COc1cccc(NC(=O)OC2CN3CCC2CC3)c1
Yield: 60 %

Procedure:
3-Quinuclidinol and 3-methoxyphenyl isocyanate were used. The reaction solution was evaporated under reduced pressure, and the residual solid was recrystallized from ethyl acetate to afford the title compound (60%) as a white solid: mp 130.5-132.0° C.; FAB LRMS m /z (relative intensity, %) 278 (18), 277 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCC(=O)O
Product: CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and butyric acid to yield (3aR,4S,7aR)-4-butyryloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.40 min; UPLC Method I
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)[C:25]=1[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:27]=[C:28]([C:30]([F:31])([F:33])[F:32])[N:29]=2)[C:25]=1[CH3:26])[CH3:2]
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Br)ccc2nc(C(F)(F)F)cn12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc2nc(C(F)(F)F)cn2c1C
Yield: 24.2 %

Procedure:
A mixture of 0.52 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.56 g of 6-bromo-5-methyl-2-trifluoromethylimidazo[1,2-a]pyridine, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylphenyl, 0.84 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred under heat-reflux for 3 hours. 0.1 ml of water was added to the cooled reaction mixture, and the mixture was stirred under heat-reflux for 5 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The dried matter was concentrated under reduced pressure, and then the resulting residue was applied to a silica gel column chromatography to obtain 0.16 g of 6-(2-ethylsulfanylphenyl)-5-methyl-2-trifluoromethylimidazo [1,2-a]pyridine (Compound of Present Invention 28).