Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:29])=[CH:13][N:12]=3)=[CH:9][N:8]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:5]2=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH:20]1[CH2:19][CH:18]([NH:17][C:15]2[C:14]([F:29])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:8]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:9]=3)[N:16]=2)[CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Temperature: 80 °C

Procedure:
A suspension of tert-butyl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6b, (0.23 g, 0.40 mmol) in methanol (10 mL) was treated with 4N HCl/dioxane (5 mL, 20 mmol) then heated at 80° C. for 30 minutes.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH3:31])[CH:21]=1.[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:39]=1)([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:40]3[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=3)[C:37]([NH:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:51])[CH2:50][CH2:49]2)=[O:26])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (6.31 g, 9.92 mmol, 5.91 ml) was added dropwise to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1 g, 5 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.5150 g, 5,5 mol) and triethylamine (1.508 g, 14.88 mmol, 2.068 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.71 g). MS (ESI) m/z 459.7 [M+H]+
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O[CH:8]=[N:9][C:10]1[S:18][C:17]2[CH2:16][CH2:15][N:14]([CH2:19][CH3:20])[CH2:13][C:12]=2[C:11]=1[C:21](OCC)=[O:22])C>C(O)C>[OH:2][CH2:1][CH2:3][N:4]1[C:21](=[O:22])[C:11]2[C:12]3[CH2:13][N:14]([CH2:19][CH3:20])[CH2:15][CH2:16][C:17]=3[S:18][C:10]=2[N:9]=[CH:8]1
Reactant: NCCO
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CN(CC)CC2
Solvent: CCO
Product: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Yield: 63 %

Procedure:
5.0 ml (81 mM [sic]) of ethanolamine were added to 17.0 g (55 mM [sic]) of 2-ethoxymethyleneamino-3-carboethoxy-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine in 130 ml of ethanol and then refluxed for 2 h. The mixture was then concentrated to a volume of about 50 ml and stirred in an ice bath. The precipitated fine solid was filtered off with suction and washed with cold ethyl acetate. 10.5 g (63%) of pale brown product were isolated.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([OH:23])=[O:22])([OH:3])=[O:2].Cl.[CH2:25](O)[CH3:26]>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:11])[N:6]([CH3:19])[C:5]=1[CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])([OH:3])=[O:2]
Reactant: CCO
Reactant: Cc1ccc(C(=O)c2c(C)c(C(=O)O)c(CC(=O)O)n2C)cc1
Agent: Cl
Product: CCOC(=O)Cc1c(C(=O)O)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 37 g. (0.118 mole) of 3-carboxy-1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid in 370 ml. of ethanol containing 1.8 g. of dry hydrogen chloride is heated under reflux for 45 min. The solution is cooled and the solid which precipitated, ethyl 3-carboxy-1,4-dimethyl-5-(o-toluoyl)-pyrrole-2-acetate, is collected, m.p. 200°-202°C.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[ClH:17]>>[Cl:17][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: OC1c2ccccc2CSc2ccccc21
Reactant: Cl
Product: ClC1c2ccccc2CSc2ccccc21
Reaction time: 72 h

Procedure:
A solution of 33 g of 11-hydroxy-6,11-dihydrodibenz[b,e]thiepin in 400 ml of absolute alcohol is saturated with hydrogen chloride gas at 5° C. for 1/2 hour. The resulting solution is dried with CaCl2, filtered and concentrated in vacuo to an oil which crystallizes upon standing in a refrigerator (10° C.) after 3 days. Recrystallization from cyclohexane provides 27 g of 11-chloro-6,11-dihydrodibenz[b,e]thiepin m.p. 79°-82° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH2:18])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11])([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)ccc2C(C)(C)C)c1
Yield: 61.1 %

Procedure:
Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[Br:12]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:12][C:8]1[C:7]([O:10][CH3:11])=[CH:6][C:4]([NH2:5])=[C:3]([Cl:2])[CH:9]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.5 %

Procedure:
A stirred solution of 9.7 g (0.050 mole) of 2-chloro-5-methoxyaniline hydrochloride in 120 mL of acetic acid was cooled to 15° C. To this cold mixture was added 4.0 g (0.025 mole) of bromine. After complete addition, the mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was poured into ice water. To the resultant mixture was added a solution of 2.0 g (0.05 mole) of sodium hydroxide in 10 mL of water. This mixture was extracted with 200 mL of diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 7.3 g of 4-bromo-2-chloro-5-methoxyaniline as a solid, mp 40°-41° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:16]([C:22](OCC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:23]=[C:22]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cccnc1Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1nc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 57.7 %

Procedure:
11.68 g (63 mmol) of 3-amino-2-anilinopyridine was dissolved in ethanol (150 mL), and 12.07 g (69 mmol) of diethyl ketomalonate was added thereto. The mixture was heated to reflux for 4 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue thus obtained was washed using diisopropyl ether, to obtain 10.74 g (yield: 58%) of ethyl 3-oxo-4-phenyl-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1([CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=2)[CH2:18][NH2:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=1)[CH2:16][C:13]1([C:12]([F:11])([F:30])[F:31])[CH2:15][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyridin-5-yl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=451.1, tR (minutes, Method G)=2.50. [α]D20=+33.55 (c=3.07 mg/mL,CHCl3)
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H:18]2[C@@H:22]([O:23][CH2:24]C)C[N:20]([C:26]3SC=C[N:30]=3)[CH2:19]2)=NC=1CC.[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][NH:53][CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49].ClC1N=C(OC)C=CN=1>>[Cl:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:59][CH3:60])[C:45]([NH:50][C@H:51]2[C@@H:55]([O:56][CH2:57][CH3:58])[CH2:54][N:53]([C:26]3[N:30]=[C:22]([O:23][CH3:24])[CH:18]=[CH:19][N:20]=3)[CH2:52]2)=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: COc1ccnc(Cl)n1
Product: CCO[C@H]1CN(c2nccc(OC)n2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine and 2-chloro-4-methoxypyrimidine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.03, 7.25, 7.02, 6.90, 6.02, 5.25, 4.88, 4.22, 3.92–3.78, 3.55, 2.74, 2.50, 1.33–1.26, 1.16; IR (diffuse reflectance) 2972, 2475 (w), 2350 (w), 2310 (w), 2183 (w), 2069 (w), 1585 (s), 1568 (s), 1516 (s), 1482 (s), 1466 (s), 1397, 1393, 1292, 1231 cm−1 HRMS (ESI) calcd for C26H33N6O3Cl+H1 513.2380. found 513.2356.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[F:31][C:32]([F:36])([F:35])[CH2:33]I.Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:33][C:32]([F:36])([F:35])[F:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 505.2 %

Procedure:
To a stirred solution of NaH (64 mg, 0.13 mmol) in DMF (15 mL) was added ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (500 mg, 0.12 mmol) and 1,1,1-trifluoro-2-iodoethane (0.304 mL, 0.15 mmol) at 0° C. The reaction mixture was stirred at 0° C. over a period of 30 min. After completion of starting material (by TLC), diluted with water (20 mL), acidified with 1N HCl (pH=5) and extracted with EtOAc (3×30 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (300 mg) as liquid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.N1C=CN=C1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CSc1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Agent: c1c[nH]cn1
Solvent: ClCCCl
Solvent: CC#N
Product: CSc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylsulfanyl-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step B, 400 mg, 1.6 mmol, 1.0 eq.) in anhydrous CH3CN (30 mL) was added dropwise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (900 mg [slightly contaminated with imidazole], 1.6 mmol, 1.0 eq.) in 20 mL of anhydrous CH3CN. The reaction was stirred for 16 h at RT then EDC (0.5 g, 2.6 mmol, 1.5 eq.) was added. The resulting mixture was heated to 80° C. for 1 h. The solvent was evaporated and the residue was diluted with CH2Cl2 (25 mL). The solution was washed with H2O (25 mL), NaHCO3 (25 mL, aq.) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-7.5% MeOH/CH2Cl2) to give pure [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylsulfanyl-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=496.2 (M+H)+; MW Calc'd for C24H26N7OS: 495.16.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([F:42])[C:38]=1B(O)O>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[C:37]([F:42])=[CH:36][N:35]=[CH:34][C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: OB(O)c1c(F)cncc1F
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cncc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3,5-difluoropyridin-4-yl)boronic acid gave 247. LCMS (ES+) m/z 453 (M+1).
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.[C:12]1(=[CH:16][C:17](O)=[O:18])[CH2:15][CH2:14][CH2:13]1.Cl>>[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]2[C:5]=1[C:17](=[O:18])[CH2:16][C:12]1([O:11]2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)C=C1CCC1
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: O
Product: O=C1CC2(CCC2)Oc2cc(O)cc(O)c21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
8 g (49.34 mmol) of 1,3,5-trihydroxybenzene dihydrate and 6.64 g (59.21 mmol) of cyclo-butylideneacetic acid (Example 40A) are initially charged, 25 ml (197.4 mmol) of boron trifluoride/diethyl ether complex are added and the mixture is then heated to 70° C. After three hours, the mixture is cooled, poured into 600 ml of ice-water, acidified with 6 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is taken up in dichloromethane and stirred, and insoluble solid is then filtered off. Silica gel is added to the filtrate, the mixture is concentrated and the residue is purified chromatographically on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This gives 4.7 g (43% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH:11]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[N+:23]([O-])=O)([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][C:2]([CH:11]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[NH2:23])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
α-Methyl-[2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (6.80 g; 14.9 mmole) was dissolved in methanol (200 ml) under argon at room temperature. Powdered stannous chloride dihydrate (17.48 g; 77.5 mmole) was added, followed by concentrated hydrochloric acid (19 ml) with stirring. After 1.5 hours, Celite, ethyl acetate and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a Celite pad. The pad was then rinsed with ethyl acetate (three times). The filtrate was concentrated and the resulting white solid was triturated with 10% methanol:water and dried giving 6.02 g of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][CH2:10][OH:11].C1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][C:37]3[C:46]4[C:41](=[CH:42][C:43]([O:47][CH3:48])=[CH:44][N:45]=4)[N:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[N:21][N:20]=1>>[CH3:48][O:47][C:43]1[CH:42]=[C:41]2[C:46]([C:37]([S:36][C:33]3[CH:34]=[CH:35][C:30]([NH:29][C:22]4[C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]([O:11][CH2:10][CH2:9][CH:4]5[CH2:5][CH2:6][CH2:7][CH2:8][NH:3]5)=[N:20][N:21]=4)=[CH:31][CH:32]=3)=[CH:38][CH:39]=[N:40]2)=[N:45][CH:44]=1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: OCCC1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(OCCC5CCCCN5)c5ccccc45)cc3)ccnc2c1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Sodium Hydride (11 mg, 449 μmol), 2-(piperidin-2-yl)ethanol (58 mg, 449 μmol), and benzene (2243 μl, 449 μmol) were combined in a resealable tube capped with a septum and heated to 40° C. for 30 minutes. 4-Chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (200 mg, 449 μmol) was added, and the reaction mixture was allowed to stir at 80° C. for 18 hours. The mixture was concentrated in vacuo and the crude material was partitioned between methylene chloride and water. The organic layers were combined and over Na2SO4 and concentrated. The crude material was purified via ISCO, 12 g RediSep column eluting with a 20-100% gradient of 90:10:1 (DCM:MeOH:NH4OH) in DCM. The product fractions were combined and concentrated in vacuo to afford N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)-4-(2-(piperidin-2-yl)ethoxy)phthalazin-1-amine MS: [M+H]=539.
Reaction SMILES: [Na].C(O[C:5](=[O:14])[CH2:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)C.O.[F:16][C:17]([F:22])([F:21])[CH2:18][NH:19][NH2:20]>C(O)(=O)C>[F:16][C:17]([F:22])([F:21])[CH2:18][N:19]1[C:5](=[O:14])[CH2:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:20]1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: NNCC(F)(F)F
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1=NN(CC(F)(F)F)C(=O)C1

Procedure:
1 Mole (221 g) of the sodium salt of oxalacetic diethyl ester and 1 mole (224 g) of 2,2,2-trifluoroethylhydrazine hydrate were stirred for 1 hour in 1 l of boiling acetic acid. The mixture was poured out on water and stirred. The product melting at 171° C. was filtered with suction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
57.5 g (0.18 M) of (S)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 600 ml of absolute acetone. The solution is treated with 48 g of powdered potassium carbonate and 21 ml of methyl iodide and stirred at room temperature for 5 hours. The mixture is concentrated and the residue is treated with ice-water and extracted several times with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ether/petroleum ether and there is obtained (S)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 118°-126° C. with decomposition; [α]25D =+563.1° (in methylene chloride; 1%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([S:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:44])=[O:43])[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(N2CCN(S(=O)(=O)Cc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in 1,4-dioxane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and phenylmethanesulfonyl chloride (0.25 mmol). The reaction was stirred at 90° C. for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (13 mg) which was characterized by its mass spectrum: MS m/z (%): 513 ([M+H]+, 100).
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]([CH3:28])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH:23]([NH:25][CH3:26])[CH2:22][C:21]4=[O:27])=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([CH2:26][NH:25][CH:23]1[CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:28])[C:11](=[O:12])[C:10]3[CH:29]=[CH:30][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)=[CH:15][CH:16]=2)[C:21](=[O:27])[CH2:22]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1
Solvent: c1ccncc1
Product: CC(=O)CNC1CC(=O)N(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1

Procedure:
4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidin-1-yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).