Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[N:6]1)[CH2:2][C:3]#[CH:4].[CH2:14]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19]1)[CH2:15][C:16]#[CH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1>CN(C=O)C.[Cu]I.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.CCN(CC)CC>[N:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:26]=1[C:4]#[C:3][CH2:2][CH2:1][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[N:6]1.[N:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:17]#[C:16][CH2:15][CH2:14][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19]1
Reactant: C#CCCn1cc2ccccc2n1
Reactant: Brc1ccccn1
Reactant: C#CCCn1ncc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1ccccn1)CCn1cc2ccccc2n1
Product: C(#Cc1ccccn1)CCn1ncc2ccccc21
Temperature: 120 °C
Yield: 3 %
Yield: 2 %

Procedure:
A solution of 2-(but-3-ynyl)-2H-indazole and 1-(but-3-ynyl)-1H-indazole (160 mg, 0.94 mmol) in DMF (0.5 mL) was added to a suspension of CuI (8.9 mg, 47 μmol), Et3N (2.5 mL), Pd(PPh3)2Cl2 (33 mg, 47 μmol), PPh3 (6.2 mg, 23 μmol) and 2-bromopyridine (149 mg, 0.94 mmol). The reaction mixture was heated at 120° C. for 900 s in a microwave. The reaction mixture was quenched with water, Et3N was evaporated and the aqueous phase was extracted with DCM. The organic phase was washed with a saturated solution of NH4OH, brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2, DCM/MeOH/NH4OH 95:4:1 to 94:4:2) to yield 6.8 mg (27 μmol, 3%) of 2-(4-(pyridin-2-yl)but-3-ynyl)-2H-indazole as a yellow solid and 4.6 mg (19 μmol, 2%) of 1-(4-(pyridin-2-yl)but-3-ynyl)-1H-indazole as an orange oil.
Reaction SMILES: CS(O)(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17]O)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]2[N:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]([CH2:15][CH2:16][CH2:17][N:33]3[CH2:32][CH2:31][CH:30]([N:26]4[C:25]5[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][C:24]=5[NH:28][C:27]4=[O:29])[CH2:35][CH2:34]3)[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 7.6 parts of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 5.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5 parts of sodium carbonate and 63 parts of N,N-dimethylformamide is stirred and heated in an oil-bath at 50°-60° C. for 2 hours. The reaction mixture is poured onto water. The precipitated product is filtered off, dried and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water. It is filtered off again and dissolved in a mixture of 4-methyl-2-pentanone and a small amount of N,N-dimethylformamide. The solution is filtered till clear and the filtrate is concentrated to a volume of about 10 parts. The concentrate is triturated in methanol. The precipitated product is filtered off and dried, yielding 1.27 parts of 5-chloro-1-{3-[4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 229°-236° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)=[O:3].[BH4-].[Na+]>CO>[CH3:1][CH:2]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][CH:9]=1)[OH:3]
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(-c2ccccc2)nc1-c1ccccc1

Procedure:
To a mixture of 41.1 g (0.15 mole) of 2,4-diphenyl-5-pyrimidyl methyl ketone in 500 ml methanol stirred at 5°-10° was added over 20 minutes 11.4 g (0.30 mole) sodium borohydride. The resulting solution was stirred at 5°-10° for 30 minutes and then stirred at ambient temperatures for 2 hours. The solvents were removed in vacuo and the residue was partitioned between 500 ml CHCl3 and 500 ml water. The aqueous layer was extracted with two 500 ml portions of CHCl3. The combined CHCl3 extracts were washed with 250 ml water, dried (MgSO4), and concentrated to dryness in vacuo.
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6]Cl.C([O-])(=[O:13])C.[Na+].C[O-].[Na+].O>CN(C)C=O.CO>[Cl:1][CH:2]=[C:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][O:13]1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C=C(Cl)Cl)CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)CCOC1=CCl
Temperature: 100 °C
Yield: 89 %

Procedure:
806 g (4 moles) of 1,1,5-trichloro-3,3-dimethyl-1-pentene are heated under reflux with 360 g (4.4 moles) of anhydrous sodium acetate in 1 liter of dimethylformamide for 6 hours. After cooling to about 100° C., 1.6 liters (8 moles) of 30% strength sodium methylate solution in methanol are added dropwise and the mixture is heated under reflux for a further 4 hours. The cold solution is poured into water and extracted several times with methylene chloride. After the solution has been dried and the solvent has been distilled off, 654 g of product remain, and are fractionated over a column. 522 g (89% of theory) of 2-chloromethylene-3,3-dimethyl-tetrahydrofuran of boiling point 84°-87° C./20 mbar are obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:8]2[CH2:9][CH2:10][C@@H:4]([C@@H:5]3[C@H:7]2[CH2:6]3)[C@H:3]1[C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:1][C@H:2]2[C@@H:8]3[CH2:9][CH2:10][C@@H:4]([C@@H:5]4[C@H:7]3[CH2:6]4)[C@H:3]2[C:11]([O:13][CH3:14])=[O:12])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H]1[C@@H](N)[C@@H]2CC[C@H]1[C@H]1C[C@H]12
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1[C@H]2CC[C@H]([C@@H]3C[C@@H]32)[C@@H]1NCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The crude rac-Methyl (1R,2R,4S,5S,6R,7S)-7-aminotricyclo[3.2.2.02,4]nonane-6-carboxylate was dissolved in methanol (10 mL). Acetic acid (0.12 mL, 2.14 mmol) was added followed by 4-fluoro-benzaldehyde (0.12 mL, 1.07 mmol). Sodium cyanoborohydride (0.14 g, 2.14 mmol) was added and the mixture was stirred at 60° C. for 16 h. The mixture was cooled to 25° C. and poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate, as a clear oil, which was used in the next step without further purification. LC-MS (ESI) calcd for C17H22FNO2 291.36, found 292.0 [M+H+].
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[S:11])=[O:7])(C)(C)C.C(OC(NNC(=O)C1C=CC(F)=CC=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[F:53][CH:54]([F:64])[O:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH:58]=O.[F:65][C:66]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[C:67]=1C(Cl)=O>C(Cl)Cl>[F:53][CH:54]([F:64])[O:55][C:56]1[CH:63]=[CH:62][CH:61]=[CH:60][C:57]=1[CH:58]1[N:8]([C:6]([C:67]2[C:66]([F:65])=[CH:74][C:73]([F:75])=[CH:72][C:71]=2[F:76])=[O:7])[N:9]=[C:10]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[S:11]1
Reactant: O=Cc1ccccc1OC(F)F
Reactant: Cc1ccc(C(=S)NNC(=O)OC(C)(C)C)cn1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Agent: CC(C)(C)OC(=O)NNC(=O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C2=NN(C(=O)c3c(F)cc(F)cc3F)C(c3ccccc3OC(F)F)S2)cn1
Reaction time: 16 h

Procedure:
N′-(6-Methyl-pyridine-3-carbothioyl)-hydrazinecarboxylic acid tert-butyl ester (0.1 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (1 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. Solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.287 mmol) is added to the solution and the mixture is treated with 2-difluoromethoxy-benzaldehyde (0.12 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes. The mixture is kept at ambient temperature for 16 hours and purified by preparative HPLC (20-100% MeCN/H2O) to yield [2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone: 1H NMR (400 MHz, CDCl3) 8.71 (d, J=2.1 Hz, 1H), 7.81 (dd, J1=8.2 Hz, J2=2.2 Hz, 1H), 7.53 (s, 1H), 7.36-7.4 (m, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.3 Hz, 1H), 6.78 (t, J=8.3 Hz, 2H), 6.67 (dd, J1=75.0 Hz, J2=71.7 Hz, 1H), 2.64 (s, 3H); LC/MS (ES+): (M+1) 480.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)=[CH:13][N:12]=2)[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[NH2:25][C:26]([CH3:37])=[CH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:29].[Cl:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH:41]=O>C(O)C>[Cl:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH:41]1[C:27]([C:28](=[O:29])[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:26]([CH3:37])[NH:25][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:3]3[C:4]4[CH:9]=[CH:8][N:7]=[CH:6][C:5]=4[N:10]=[C:2]3[CH3:1])=[N:12][CH:13]=2)=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Reactant: CC(N)=CC(=O)Nc1ccccn1
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)nc2)NC(C)=C(C(=O)Nc2ccccn2)C1c1ccccc1Cl
Reaction time: 0.75 h

Procedure:
A solution of ethyl 2-(2-methylimidazo[4,5-c]pyrid-1-yl)pyrid-5-oylacetate (324 mg, 1.0 mmol), 3-amino-N-(2-pyridyl)but-2-enamide (178 mg, 1.0 mmol) and 2-chlorobenzaldehyde (140 mg, 1.0 mmol) in ethanol (4 ml) was heated under reflux for 5 hours under nitrogen. The solution was cooled and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate:methanol, 6:1), followed by sonication of a suspension of the eluted product in ether/ethyl acetate, 3:1 for 45 minutes. The off-white solid product was filtered off and dried in vacuo to give the title compound, 140 mg (23%), m.p. 242°-3° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1C(NN)=O.C[CH2:17][OH:18].Cl.[N:20]([O-])=O.[Na+]>O>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[NH:20][C:17](=[O:18])[NH:1][C:2]=3[N:7]2[N:8]=1
Reactant: CCO
Reactant: O=N[O-]
Reactant: Cc1cc2ncc(C(=O)NN)c(N)n2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc2ncc3[nH]c(=O)[nH]c3n2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 100 mL flask containing Compound (10-1) (1.1 g, 5.0 mmol, 1 eq.), EtOH (25 mL), and 10% aqueous HCl (25 mL) was cooled to 0° C. by ice-water bath. Then NaNO2 (0.35 g, 5.0 mmol, 1 eq.) in water (8 mL) was added slowly. The mixture was stirred at that temperature for 2 hours, after which it was heated to 80° C. for 2 hours. After cooling and removal of the volatiles by rotary evaporation, the residue was treated with water (40 mL). The resulting precipitated solid was filtered and washed with water (2×5 mL) to provide Compound (10-2) as a brownish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=C)=[CH:34][CH:33]=1)#[N:31]>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:36][C:35]3[CH:38]=[CH:39][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(C#N)cc1
Product: CC(C)(Cc1c[nH]c2c(C=Cc3ccc(C#N)cc3)cccc12)NC(=O)OC(C)(C)C

Procedure:
(2-{7-[2-(4-Cyano-phenyl)-vinyl]-1H-indol-3-yl}-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 4-cyanostyrene as described for the preparation of Amine 23 (93%). FDMS m/e=315.2 (M++1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:11][CH:12]1[CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:13]1[CH2:14][CH:12]1[CH2:11][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: BrCC1CO1
Reactant: c1ccc2c(c1)CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CN(CC1CO1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of isoindoline (200 mg, 1.68 mmol) and 2-(bromomethyl)oxirane (272 mg, 2.0 mmol) in CH3CN (10 mL) was added K2CO3 (690 mg, 5 mmol) and reaction mixture was stirred at 25° C. for 16 h. The mixture was filtered, concentrated and the crude product was used in the next step without further purification. (280 mg, yield 95%) MS (ESI+) e/z: 176.1 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([OH:34])=[O:33])[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1.[N:52]1([CH2:58][CH2:59]O)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:35][C:36]3[CH:41]=[C:40]([C:42]([F:43])([F:45])[F:44])[C:39]([NH2:46])=[C:38]([Cl:47])[CH:37]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[C:32]([O:34][CH2:59][CH2:58][N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:33])[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:48]=[CH:49][CH:50]=[CH:51][C:4]=2[NH:3]1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)O)CC2)cc1C(F)(F)F
Reactant: OCCN1CCOCC1
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC[C@@H]3C(=O)OCCN3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 9.2 from 50 mg (0.07 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-((R)-2-carboxy-pyrrolidin-1-yl) -piperidin-1-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 10.3 mg (0.08 mmol) 2-morpholin-4-yl-ethanol.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([C:28]#[N:27])=[CH:30][CH:31]=3)=[O:25])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCc3ccc(C#N)cc3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and p-(aminomethyl)benzonitrile hydrochloride and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH:13]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][N:11]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[CH:23][N:22]=2)[C:10]1=[O:31].[Cl:32]CCl>>[ClH:32].[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][N:11]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[CH:23][N:22]=2)[C:10]1=[O:31]
Reactant: ClCCl
Reactant: CN1C(=O)N(c2cc(C(F)(F)F)ncn2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cc(C(F)(F)F)ncn2)CC1C(=O)O
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (800 mg, 4.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 4-chloro-6-(trifluoromethyl)pyrimidine (729 mg, 4.00 mmol) in 1,4-dioxane (40 ml) was treated with cesium carbonate (1953 mg, 5.99 mmol), Xantphos™ (173 mg, 0.300 mmol) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.100 mmol) and the reaction mixture was heated at reflux under argon overnight. After cooling the reaction was diluted with water and extracted with ethyl acetate (×2). The organic layers were combined and washed with water and brine, dried over anhydrous sodium sulfate and reduced under vacuum. The residue was purified by Flashmaster automated silica gel chromatography eluting with 0-30% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (983 mg, 67.5% yield). LC/MS [M+H]+=347. (ii) Trifluoroacetic acid (4 ml, 51.9 mmol) was added to a solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylate (980 mg, 2.83 mmol) in dichloromethane (8 ml) and the solution was stirred at room temperature for 6 hours. The solvent was evaporated and the residue was co-evaporated with toluene. The residue was dissolved in saturated sodium hydrogen carbonate solution and the solution was loaded onto an amino column eluting with 10% 2N hydrochloric acid in methanol. Product-containing fractions were combined and reduced under vacuum and the residue was triturated with methanol and the solid was filtered off. The filtrate was reduced under vacuum to give 3-methyl-2-oxo-1-[6-(trifluoromethyl)-4-pyrimidinyl]-4-imidazolidinecarboxylic acid hydrochloride salt (893 mg, assume ˜2.8 mmol) which was used in the next step. LC/MS [M+H]+=291.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[F:21])[NH2:17].C(N(CC)CC)C.[CH3:29][C:30]1[C:38]2[C:37]([N:39]3[CH2:44][CH2:43][NH:42][C@@H:41]([CH3:45])[CH2:40]3)=[N:36][CH:35]=[N:34][C:33]=2[NH:32][CH:31]=1>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:5]([N:42]2[CH2:43][CH2:44][N:39]([C:37]3[C:38]4[C:30]([CH3:29])=[CH:31][NH:32][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:40][C@@H:41]2[CH3:45])=[O:11])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: Nc1ccc(F)c(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CCN(C(=O)Nc4ccc(F)c(Br)c4)[C@@H](C)C3)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.5 %

Procedure:
To a solution of triphosgene (0.30 g, 1 mmol) in CH2Cl2 (70 ml) at −5° C. were added 3-bromo-4-fluoroaniline (0.19 g, 1 mmol) in CH2Cl2 (20 ml) and triethylamine (0.60 ml, 4.3 mmol). The reaction was stirred at room temperature for 20 min, then (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine from step B (0.23 g, 1 mmol) in CH2Cl2 (30 ml) was added. The mixture was stirred for 1.5 hours, then concentrated under vacuum. The residue was purified by prep HPLC to afford (S)—N-(3-bromo-4-fluorophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (65 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:19])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+].C[O-].[Na+]>ClCCl>[F:19][C:7]1[CH:6]=[C:4]([NH:5][C:27](=[O:29])[CH3:28])[CH:3]=[C:2]([F:1])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: CC(=O)Cl
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(F)c(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
1.60 g (6.14 mmol) of 3,5-difluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline are suspended in 45 ml of dichloromethane and cooled to 0° C. 2.57 ml (18.4 mmol) of triethylamine and 0.87 ml (12.3 mmol) of acetyl chloride are added dropwise, and stirring at 0° C. is continued for 2.5 hours. A further 0.86 ml (6.14 mmol) of triethylamine and 0.44 ml (6.14 mmol) of acetyl chloride are added, and the mixture is allowed to react for another hour. Saturated sodium bicarbonate solution is then added, and the mixture is stirred at RT for 10 min. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure. The crude product is taken up in 45 ml of ethanol. 1.14 ml (6.14 mmol) of 5.4M sodium methoxide solution are added, and the mixture is stirred at RT for 30 min. The mixture is concentrated and the product is purified by chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 100:5).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:13]1CCCC[CH2:14]1.N1C=NC=NC=1>C(O)C>[F:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[F:11])[N:1]=[CH:14][NH:13][C:4]2=[O:5]
Reactant: C1CCNCC1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: c1ncncn1
Solvent: CCO
Product: O=c1[nH]cnc2cc(F)c(F)cc12
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of 4.81 g (27.8 mmol) of commercially available 2-amino-4,5-difluorobenzoic acid in 20 ml of ethanol were added 1.92 ml (19.4 mmol) of piperidine and 2.25 g (27.8 mmol) of 1,3,5-triazine, followed by heating under reflux in an atmosphere of argon for 6.5 hours. After the reaction mixture was allowed to cool to room temperature, the solvent was evaporated. To the residue was added water, and the resulting mixture was neutralized with 4 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 4.37 g (86%) of 6,7-difluoro-4(3H)-quinazolone.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][C:20]([O:22]CC)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][C:20]([OH:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)Cc1nc2ccccc2n1Cc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CC(=O)O)Cc1nc2ccccc2n1Cc1ccccc1
Yield: 64 %

Procedure:
9 g of ethyl 4-(1-benzylbenzimidazol-2-yl)-3,3-dimethylbutanoate, prepared in Example 47, are dissolved in a mixture composed of 90 ml of concentrated hydrochloric acid, 270 ml of water and 250 ml of acetic acid. The mixture is refluxed for 4 hours and the solvents are concentrated under vacuum. The residue is taken up with a 1N solution of sodium hydroxide and the resulting mixture is washed with ether; the aqueous phase is acidified by having sulfur dioxide bubbled through it until the pH is 5-6, and the crystals formed are filtered off and washed with water and isopropyl ether to give 5.3 g of 4-(1-benzylbenzimidazol-2-yl)-3,3-dimethylbutanoic acid in the form of crystals melting at 160°-1° C.