Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH2:39]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][CH2:37][CH2:38][NH:39][CH2:2][C:3]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6]1)=[O:4]
Reactant: NCCNc1ccccn1
Reactant: COC(=O)CC1CCN(C(=O)CBr)Cc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(C(=O)CNCCNc2ccccn2)Cc2ccccc21
Reaction time: 18 h

Procedure:
To a stirring solution of methyl 2-(2-(2-bromoacetyl)-1H,3H,4H,5H-benzo[e]azepin-5-yl)acetate in THF (0.2 M), was added diisopropylethylamine (1.5 eq) and 2-(2-pyridylamino)-1-aminoethane (1.2 eq). The reaction was stirred for 18 hr, followed by concentration by rotary evaporation and the product was purified by flash chromatography (10% MeOH/CH2Cl2). EI-MS m/z 397 (M−H)−
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8](=[O:11])[C:22]1[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=1)[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)c(F)c1)NC(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.1 g) in tetrahydrofuran (100 mL), 3,4,5-trifluorophenylmagnesium bromide (0.35 M solution in diethyl ether; 55 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. for five hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the solution. The reaction solution was heated to room temperature, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane->heptane:ethyl acetate=1:1) to obtain 4.8 g of ethyl (R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate. A solution of 4 N hydrochloric acid in ethyl acetate (30 mL) was added to a solution of the resulting ethyl(R)-2-tert-butoxycarbonylamino-5-oxo-5-(3,4,5-trifluorophenyl)pentanoate in ethyl acetate (30 mL), and the solution was stirred for 15 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. 10% palladium-carbon (100 mg) was added to a solution of the residue in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen stream at 1 atm for six hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 2.91 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:4]=1[O:5][CH2:6][CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])#[N:2].N1C=C[CH:30]=[CH:29][CH:28]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:30]([O:9][C:8](=[O:10])[CH:7]([O:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][O:5][C:4]1[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:3]=1[C:1]#[N:2])[CH:29]=[CH2:28]
Reactant: c1ccncc1
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCC(Oc1ccccc1Cl)C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)C(COc1ccc(C(F)(F)F)cc1C#N)Oc1ccccc1Cl
Reaction time: 3 h

Procedure:
55 g (0.15 Mol) of the acid obtained in Example 2 are dissolved in 120 ml of toluene. Then 2 ml of pyridine and 40 ml of thionyl chloride are added thereto. This mixture is stirred for 3 hours at 80°. Then the solvents are distilled off under reduced pressure and the remaining oil (56 g) is dissolved in 200 ml of toluene. To this solution is added dropwise, at a temperature of 5°-15°, first 12.5 g of allyl alcohol, then 28 g of triethylamine. This reaction mixture is stirred overnight at room temperature and then added with 50 ml of water. The organic phase is separated, dried over sodium sulfate, filtered and then evaporated to dryness. The residue represents 57.8 g of a dark oil, which is dissolved in toluene and cleaned by chromatography over an alumina oxide column. After evaporation of the toluene and distillation, there remains 54 g of the allyl ester as a clear oil, b.p. 165° /0.01 torr.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H:19](C(O)=O)[CH2:18]N1.ICC.[H-].[Na+]>CN(C)C=O>[CH2:18]([N:4]1[CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:14])[CH3:19]
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Reactant: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1C(=O)N(C)CC1C(=O)OC(C)(C)C
Temperature: -10 °C
Yield: 76 %

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (0.501 g, 2.5 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) was cooled to −10° C. under argon and treated with iodoethane (0.404 ml, 5.00 mmol). Sodium hydride (60% dispersion in oil) (0.100 g, 2.500 mmol) was added portion wise. The mixture was allowed stirred warm to room temperature over 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml) and the organic extracts were combined, washed with saturated sodium hydrogen carbonate solution (20 ml), water (2×20 ml) and brine (20 ml), dried and evaporated. The residue was purified by silica gel chromatography eluting with 25-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 76%). LC/MS [M+H]+=229. (ii) A solution of 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 1.897 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 18 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylic acid, (assume ˜1.9 mmol). LC/MS [M+H]+=173.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.CCCCCC.Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH3:14][O:13][CH2:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCOc1cccc(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(OCOC)cccc1OCOC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 1,3-bis{[(methyloxy)methyl]oxy}benzene (Intermediate 79, 2.19 g) in dry tetrahydrofuran (10 ml) at room temperature BuLi 1.6M in hexane (8.29 ml, 13.26 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (2.263 g, 16.57 mmol) in dry tetrahydrofuran (10 ml) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml) and extracted with ethyl acetate (2×30 ml). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluent affording the title compound as a light yellow oil (1.75 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:17]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:17])[CH:6]=1
Reactant: ClCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)Oc1cc(Cl)cc2c1OC(C)(C)C2
Yield: 88.9 %

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (33.2 g, 0.15 mol) in 150 ml of chloroform and 300 ml of carbon tetrachloride, chlorine (10.7 g, 0.15 mol) was gradually fed at a temperature of from 10° to 15° C. under stirring. The precipitated crystals were collected by filtration and washed with hexane, whereby 34.1 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate was obtained. The melting of this product was 167°-169° C. The structure was confirmed by 1H-NMR spectrum. Then, the product was added to 100 ml of a 10% aqueous sodium hydroxide-methanol solution and heated at 80° C. for 3 hours. The reaction solution was neutralized with hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated, whereby 23.0 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol was obtained. The melting point of this product was 65.5°-66.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyldithiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 18) identified in Table 1 was obtained.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:13][NH:12][CH2:11]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:45]=[C:46]1[NH:55][C:54]2[N:53]=[CH:52][C:51](/[CH:56]=[CH:57]/[C:58](O)=[O:59])=[CH:50][C:49]=2[CH2:48][CH2:47]1>CN(C)C=O>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][O:9][CH:10]1[CH2:11][N:12]([C:58](=[O:59])/[CH:57]=[CH:56]/[C:51]2[CH:50]=[C:49]3[C:54](=[N:53][CH:52]=2)[NH:55][C:46](=[O:45])[CH2:47][CH2:48]3)[CH2:13]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1ccsc1COC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Reaction time: 8 h
Yield: 43 %

Procedure:
3-((3-methylthiophen-2-yl)methoxy)azetidine hydrochloride (129.0 mg, 0.6 mmol), EDCI (112.0 mg, 0.6 mmol), HOBt (82.0 mg, 0.6 mmol) and diisopropylethylamine (170 μL, 1.0 mmol) were successively added to a solution of (E)-3-(7-Oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (100.0 mg, 0.4 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight and then partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×30 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (100:0 to 95:5) as eluent. The residue was triturated in acetone to give a white solid (66.0 mg, 44%).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:37]=[C:38]([C:43](=O)[C:44]([F:47])([F:46])[F:45])[CH:39]=[C:40]([Cl:42])[CH:41]=1.O>C1(C)C=CC=CC=1>[C:11]1([S:10][CH:9]=[C:43]([C:38]2[CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]([Cl:35])[CH:37]=2)[C:44]([F:47])([F:46])[F:45])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: c1ccc(SC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C(=CSc1ccccc1)c1cc(Cl)cc(Cl)c1
Temperature: 5 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
Triphenyl[(phenylsulfanyl)methyl]phosphonium chloride (50.0 g, 116 mmol) and potassium carbonate (32.2 g, purity 98%, 233 mmol) were suspended in toluene (1 L) under an inert gas atmosphere (argon) and cooled to 5° C. 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone (29.5 g, purity 96%, 116 mmol) and polyethyleneglycole (MW 1500, 8.76 g, 5.82 mmol) were added and the reaction mixture was stirred for five and a half hours at 5° C. and after warming to room temperature stirred for additional two hours. Water (500 mL) was added and the phases were separated. The water phase was extracted with toluene and the combined organic phases were washed with water (2x) and brine. After drying over sodium sulfate, filtration and evaporation the crude mixture was treated with n-heptane (250 mL) and left in the freezer overnight. The solid was filtered off and the solvents of the filtrate were evaporated. This material was again taken up in n-heptane (100 mL) and kept in the freezer for three days. Filtration and evaporation of the solvent gave 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfide (41.6 g, 96% purity, 99% yield; E/Z=94/6—determined by GC).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: O=C(Cl)c1cnccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2cnccn2)CC1
Reaction time: 2 h
Yield: 70.7 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with pyrazine-2-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (28 mg, 68%). LCMS calculated for C20H19ClN5O2 (M+H)+: m/z=396.1; Found: 396.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(#N)C.[NH2:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:24]2[N:23]=[C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:26](=[O:27])[C:25]=2[CH:29]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
To a mixture of 1.0 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and 10 ml of acetonitrile was added 0.60 g of 2-amino-5-chloro-3-methylbenzoic acid, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture, 0.46 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.92 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.28 ml of methanesulfonyl chloride was added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.98 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([OH:32])=O)=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:29]2[C:24](=[CH:25][C:26]([C:30]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:32])=[CH:27][CH:28]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2)[C:3]1=[O:33]
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(=O)O)ccc21
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc3c(c2)C2(CCN(C(=O)/C=C/c4ccccc4C(F)(F)F)CC2)C(=O)N3C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To a solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylic acid (20 mg, 0.04 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added 1-methyl-piperazine (6.0 mg, 0.06 mmol), HOBt (12 mg, 0.09 mmol), EDCI (18 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mol) and the mixture was stirred overnight at rt under N2. The reaction mixture was washed with 1 N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by prep TLC to give (E)-1-methyl-5-(4-methylpiperazine-1-carbonyl)-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (12 mg, 57%). 1H NMR (CD3OD): 1.90 (m, 4H), 2.95 (s, 3H), 3.30 (m, 11H), 3.95 (m, 1H), 4.20 (m, 2H), 4.30 (m, 1H), 7.10 (m, 1H), 7.26 (m, 1H), 7.50 (m, 3H), 7.66 (m, 1H), 7.77 (m, 1H), 8.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[N:11]2)[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]1=2.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1.CS(C)=O.C(O[K])(C)(C)C>O>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([N:4]2[C:3]3[C:12](=[CH:13][CH:14]=[CH:15][C:2]=3[NH2:1])[NH:11][C:10]3[C:9]4[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=4[C:7]4[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=4[C:5]2=3)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1cccc2nc3c4ccccc4c4ccccc4c3nc12
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc2c1N(c1ccc([N+](=O)[O-])cc1)c1c(c3ccccc3c3ccccc13)N2
Reaction time: 24 h

Procedure:
While agitating 10.0 g (34 mmol) of 10-aminodibenzo(A,C)phenazine, 4.8 g (34 mmol) of 4-fluoronitrobenzene and 500 ml of dimethylsulfoxide, 19.4 g (173 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was charged with nitrogen, followed by agitation at room temperature for 24 hours. After completion of the reaction, 500 ml of water was added while cooling, after which the reaction solution was filtered to obtain a filtration residue. The thus obtained residue was washed with methanol to obtain the intended product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][NH:13][CH3:14])=[CH:5][N:6]2[CH3:11].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([CH3:11])[CH:5]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2cccc(F)c12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 31.3 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.11 g, 37%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1.O1CCCC1.[CH3:21][NH2:22]>>[CH3:21][NH:22][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1
Reactant: CN
Reactant: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Solvent: C1CCOC1
Product: CNCc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 60 °C

Procedure:
tert-Butyl 4-(chloromethyl)thiazol-2-ylcarbamate (8.0 g, 24.16 mmol) was dissolved in 2.0 M methylamine in tetrahydrofuran (640 mL, ˜40 eq.) and heated in the microwave for 60 minutes at 60° C. The precipitate (impurity) was filtered off and the filtrate was concentrated under reduced pressure to furnish 1.97 g product as orange foam. 1H NMR (DMSO-d6): δ 11.79 (s, br, 1H), 7.50 (s, 1H), 7.36 (d, 1H), 7.10 (m, 2H), 5.14 (s, br, 1H), 4.63 (s, 2H), 4.36 (s, 2H), 3.83 (t, 2H), 3.43 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[CH2:16][C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH2:15][CH2:16][C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CCCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 457 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 277 mg of 3-pentyn-1-ol, to which 132 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 467 mg of 4-(2-fluorophenyl)-6-(3-pentynyloxy)pyrimidine (the present compound (153)).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26]([NH2:28])=[O:27])[C:15]1([CH3:33])[CH3:32]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[NH2:28])[C:15]1([CH3:33])[CH3:32])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@H](O)CC[C@@H]1Nc1c(C(N)=O)cnn2cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](OS(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cccc12
Reaction time: 15 h

Procedure:
Triethylamine (0.131 mL, 0.936 mmol) and methanesulfonyl chloride (0.029 mL, 0.375 mmol) were added to a solution of 4-((cis-3-hydroxy-2,2-dimethylcyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (90 mg, 0.312 mmol, from Intermediate 16) in dichloromethane (5 mL). After 15 h at room temperature, the mixture was diluted with dichloromethane (60 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give crude cis-3-(3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylcyclopentyl methanesulfonate.