Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[Cl:22])O)[CH3:2].S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC.CO>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1Cl)OC
Temperature: 0 °C

Procedure:
A mixture of 3-(4-Benzyloxy-2-chloro-phenyl)-3-hydroxy-2-methoxy-propionic acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield a compound which was dissolved in methanol was treated with Mg (20 eq) and stirred until gas evolution was observed. Cooled to 0° C. and stirred for 4 hours. The solvent was removed and the residue reconstituted in ether washed with HCl 1N and brine and concentrated to give the title product.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:23])[CH:19]=[C:20](Cl)[CH3:21])[CH3:16]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:23])/[CH:19]=[C:20](/[O:14][C:10]1[CH:9]=[C:8]([CH3:7])[CH:13]=[CH:12][CH:11]=1)\[CH3:21])[CH3:16]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Cc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C)c1
Temperature: 23 °C
Yield: 63.3 %

Procedure:
Potassium t-butoxide (10.4 g, 0.092 mol) was added to a stirred solution of 3-methyl-phenol (5.00 g, 0.046 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 6.85 g, 0.046 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-m-tolyloxy-but-2-enoic acid ethyl ester (6.41 g, 63%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:35])([CH3:34])NC(=O)C(C)(C)C.NS(O)(=O)=O.[Br:41]N1C(=O)CCC1=O>ClCCl>[Br:41][CH2:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([O:10][Si:26]([CH3:35])([CH3:34])[CH3:25])=[O:9]
Reactant: CC(C)(C)C(=O)N[Si](C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 44 %

Procedure:
380.7 mg (1.09 mmoles) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were silylated by refluxing in 60 ml of dichloromethane with 320.5 mg (1.85 mmoles) of N-trimethylsilyl-2,2-dimethylpropanamide for half an hour. After the addition of 0.1 g (1 mmole) of amidosulfonic acid, the clear, slightly yellow solution was cooled in an ice-bath and bromination was carried out in half an hour using 291.4 mg (1.64 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 44% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=1>CO.C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[C:11]([NH:18][C:19](=[O:21])[CH3:20])[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:14]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1cc(N)cc(-c2ccc(F)cc2F)c1
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-nitrobiphenyl-3-yl)acetamide (4 g, 13.7 mmol) in methanol (30 ml) and ethyl acetate (15 ml) was added 10% Pd/C (400 mg, 0.1 eq.) and the reaction vessel was purged with nitrogen gas for 5 min. The mixture was then hydrogenated with H2 balloon for 12 h. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford the compound in 89% yield (3.2 g). 1H NMR (300 MHz, DMSO-d6): δ 9.77 (br s, 1H), 7.46-7.42 (m, 1H), 7.35-7.28 (m, 1H), 7.2-7.15 (m, 1H), 6.99 (br s, 1H), 8.86 (d, 1H), 6.39 (d, 1H), 5.45 (br s, 2H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[N:32]([CH3:36])[N:31]=2)=[CH:26][CH:25]=1>C(O)C>[NH2:13][C:12]1[O:35][C:33]2[N:32]([CH3:36])[N:31]=[C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[C:34]=2[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:11]=1[C:10]#[N:14]
Reactant: COc1ccc(C2=NN(C)C(=O)C2)cc1
Reactant: N#CCC#N
Reactant: O=Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(C)c3c2C(c2ccc(F)cc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 32.4 %

Procedure:
A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (586 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 19 h and the precipitate formed was washed with ethanol and hexanes, re-crystallized from ethanol, and washed with hexanes and ethanol to give 6-amino-4-(4-fluorophenyl)-3-(4-methoxyphenyl)-1-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (350 mg, 0.930 mmol, 32%) as a white solid. 1H-NMR (400 MHz) DMSO: 7.43-7.40 (d, 2H), 7.20-7.16 (m, 2H), 7.10 (s, 2H), 7.06-7.02 (t, 2H), 6.78-6.76 (d, 2H), 4.99 (s, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 13C-NMR (100 MHz) DMSO: 162.5, 159.1, 145.8, 144.6, 141.0, 141.0, 129.8, 129.7, 127.8, 125.7, 120.5, 115.6, 115.4, 113.9, 94.9, 59.7, 55.4, 3 7.4, 34.4; LC/MS-MS: 377.1→311.1 m/z; GS1 and GS2 at 30, DP=66, CE=33, CXP=20, tR=3.98 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34].[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([S:8]([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCCCC(c1cccc(-c2ccc(C(F)(F)F)cc2)n1)S(=O)c1ccc(OCC(=O)OCC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCC(c1cccc(-c2ccc(C(F)(F)F)cc2)n1)S(=O)c1ccc(OCC(=O)O)c(C)c1

Procedure:
A stirred solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)sulfinyl]phenyl}oxy)acetate (27 mg, 0.05 mmol) in THF (1 mL) and methanol (1 mL) was added, drop-wise, aqueous NaOH (2M, 1 mL). After 2 hours 50 minutes the mixture was concentrated producing a ‘chalk-white’ solid which was diluted with water (2 mL) and acidified with aqueous HCl (2M, 2 mL). The aqueous layer was extracted with DCM (2×2 mL then 1 mL) using a hydrophobic frit and the combined organic layer concentrated under vacuum yielding the title compound as a mixture of two diastereoisomers (24 mg).
Reaction SMILES: [C:1]([O:4][C:5](=O)C)(=O)[CH3:2].[F:8][CH:9]([F:18])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(OCC)(OCC)OCC.FC(F)C(OCC)=O>C(O)C.C(OCC)(=O)C>[CH2:1]([O:4][CH:5]=[C:11]([C:10](=[O:17])[CH:9]([F:18])[F:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)C(F)F
Agent: CCOC(=O)C(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)C(F)F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
427.8 g of acetic anhydride (4.15 mol) were initially charged in a stirred vessel and heated to 110° C. Within 2 hours, 438 g of crude ethyl 4,4-difluoroacetoacetate from synthesis example 2 (20.9% solution in ethanol/ethyl acetate) and 145.3 g (0.96 mol) of triethyl orthoformate were metered in in parallel. After about half had been fed in, reflux set in at 106° C. At the end of the metered addition, the internal temperature was 94° C. The mixture was stirred at reflux temperature for a further 6 hours and then cooled to 25° C. At a pressure of 150 mbar, the low boilers (ethyl acetate, acetic acid, acetic anhydride, triethyl orthoformate) were distilled off at internal temperature 40-90° C. To complete the removal, the pressure was lowered to 10 mbar at 90° C., and the distillation bottoms were subsequently stirred at 95° C./10 mbar for 1 hour. The distillation residue (125.7 g) comprised 89.7% by weight of the desired ethyl 2-ethoxymethylene-4,4-difluro-3-oxobutyrate. This corresponds to an overall yield over the two synthesis stages of 84.6% based on the ethyl difluoroacetate used in working example 2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:6]([C:9]1[CH:15]=[CH:14][C:12]([OH:13])=[CH:11][C:10]=1[OH:16])([CH3:8])[CH3:7].[H-].[Na+].[P:19](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:5]([O:1][P:19]([O:13][C:12]1[CH:14]=[CH:15][C:9]([CH:6]([CH3:8])[CH3:7])=[C:10]([O:16][P:19]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:11]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:4]1[CH:30]=[CH:31][CH:32]=[CH:2][CH:3]=1
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: C1CCOC1
Reactant: CC(C)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a tetrahydrofuran solution (10 ml) of 4-isopropylresorcinol (466 mg), sodium hydride (60% dispersion in liquid paraffin) (269 mg) was added and stirred at 0° C. for 30 minutes. Then, dibenzyl chlorophosphate (10 w/v % solution in benzene) (20 ml) was added dropwise. After stirring at room temperature for 3 hours, water (30 ml) was added to the reaction mixture, and the extraction was carried out with ethyl acetate (30 ml). Then, the extract was washed with saturated brine (20 ml), dried with anhydrous sodium sulfate and then concentrated. The residue (2.23 g) was subjected to silica gel chromatography (silica gel 76 g, chloroform to chloroform:methanol=70:1), to give 1,3-bis(dibenzylphosphonooxy)-4-isopropylbenzene (1.71 g, yield: 83%) as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[CH:24]=3)[C:15]=2[CH3:38])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[O:29][CH2:30][C:31]([OH:33])=[O:32])[C:15]=2[CH3:38])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(-c3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(C)c(-c3cccc(OCC(=O)O)c3)c3ccccn23)ccc1N
Yield: 90.2 %

Procedure:
The solution of 3.68 g (6.65 mmol) of methyl 2-amino-5-({1-[3-(2-tert-butoxy-2-oxoethoxy)phenyl]-2-methylindolizin-3-yl}carbonyl)benzoate in 11 ml of trifluoroacetic acid and 35 ml of dichloromethane at ambient temperature for 4 hours. The reaction medium is poured into water and the mixture is extracted with dichloromethane. The organic phase is partially concentrated, and the yellow precipitate formed is filtered and washed with diisopropyl ether and then dried, to give 2.75 g (92%) of a yellow powder.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:37]1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.Cl.C(N)C.C(N(CC)CC)C>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH3:37])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Agent: CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 12 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.049 mmol, 24 mg), ethylamine hydrochloride (1.22 mmol, 100 mg) and triethylamine (1.71 mmol, 239 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96i (3 mg, 12%). NMR (400 MHz, DMSO-d6) 1.21 (t, J=7.0 Hz, 3H), 1.76 (s, 6H), 2.25 (s, 3H), 3.37 (m, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.83 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.10 (s, 1H), 8.24 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=500 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=2)[C:15](=[O:17])[CH:16]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc2c(c1)c(=O)cc(-c1ccccc1)n2C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 2 grams of methyl 2-phenyl-4-quinolone-6-carboxylate (obtained in Example 1), 16 ml of methyl iodide, 2 grams of potassium carbonate and 50 ml of dimethyl formamide is stirred for four hours at 60° C. After cooling, the mixture is poured into water and extracted with ethyl acetate. From the extract ethylacetate is evaporated, the residue is purified by silica chromatography, and 1.8 grams of methyl 1-methyl-2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting point 174° to 176° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]([O:19][C:20](=O)[CH3:21])(=O)[CH3:17].[C:23](OCC)(OCC)(OCC)C>>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][N:7]([CH3:23])[CH2:6][C:5]=2[S:10][C:2]=1[N:1]=[C:16]([O:19][CH2:20][CH3:21])[CH3:17])([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(N)sc2c1CCNC2
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(N=C(C)OCC)sc2c1CCN(C)C2
Yield: 92 %

Procedure:
3.0 g (12.5 mmol) of 2-amino-3-carboethoxy-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 25 ml of triethyl orthoacetate were mixed with 0.8 ml of acetic anhydride and refluxed under nitrogen for 2 h. The mixture was then completely evaporated in a rotary evaporator at 80° C. 3.6 g (92%) of crude product were isolated as a dark oil which is sufficiently pure for the next reaction.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[NH:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17]([O-:20])(=[O:19])C.[K+].[CH3:22]O>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][O:20][C:17]([C:2]1[C:7]2[CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[NH:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: CO
Reactant: CC(=O)[O-]
Reactant: Brc1cccc2c1Cc1ccccc1NC2
Agent: [Pd+2]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1Cc1ccccc1NC2
Temperature: 125 °C

Procedure:
A mixture of 10-bromo-6,11-dihydro-5H-dibenzo[b,e]azepine (0.008 mol), potassium acetate (4 g), Pd(OAc)2 (0.04 g) and 1,1′-(1,3-propanediyl)bis[1,1-d]phenyl-phosphine (0.16 g) in methanol (100 mL) and THF (100 mL) was placed in a pressure reactor and pressurized with CO gas up to 50 kg/square cm. The reaction mixture was heated at 125° C. for 16 hours, then cooled, filtered over dicalite, and the solvent was evaporated. The residue was partitioned between CH2Cl2 and water. The organic layer was dried over MgSO4, filtered, and the filtrate concentrated. The residue was purified by column chromatography over silica gel using CH2Cl2 as an eluent. The desired fractions were collected and the solvent was evaporated, yielding 1.86 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[C:13]([NH:14][C:15]([NH2:17])=[O:16])=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([F:18])[CH:3]=1.[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:13]([NH:14][C:15]([NH:17][C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:16])=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(Br)cc1F
Reactant: CCOC(=O)C1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(F)cc2Br)CCC1

Procedure:
using isopropyl 4-bromo-2-fluoro-5-ureidobenzoate and ethyl cyclopentanon-2-carboxylate is toluene there is obtained isopropyl 4-bromo-2-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate, m.p. 166°-168° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[C:10]([Br:11])=[CH:9][N:8]=[C:7]1[CH:12]([NH:32][C:33](=[O:39])OC(C)(C)C)[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][N:18](COCC[Si](C)(C)C)[N:19]=2)[CH:15]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:57]1[CH2:62][CH2:61][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:59][CH2:58]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:5][N:6]1[C:10]([Br:11])=[CH:9][N:8]=[C:7]1[CH:12]([NH:32][C:33]([N:57]1[CH2:58][CH2:59][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:61][CH2:62]1)=[O:39])[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][NH:18][N:19]=2)[CH:15]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2c[nH]nc12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3,5-difluorobenzyl)-5-bromo-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (16.0 mg, 0.024 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (4.0 mg, 0.025 mmol, 1.1 equiv) and N′N-diisopropylethylamine (16.7 μL, 3 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (5.8 mg, 0.025, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 7.5 mg (52%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.40-1.58 (m, 4H), 2.42 (s, 3H), 2.61-2.72 (m, 2H), 3.14-3.24 (m, 2H), 3.92-4.06 (m, 2H), 4.15 (s, 2H), 4.25-4.38 (m, 1H), 4.10-5.24 (m, 2H), 5.42 (m, 1H), 6.32 (s, 1H), 6.33 (s, 1H), 6.61-6.78 (m, 3H), 6.82 (s, 1H), 6.90-6.99 (m, 1H), 7.08-7.13 (m, 2H), 7.86 (s, 1H). Mass spec.: 705.2 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH:28]=O)[CH2:24][CH2:23]2)[CH:11]=1.[OH-].[K+].[C:33](=O)([O-])[O-].[K+].[K+].C(Br)C>O.C(O)C>[Cl:1][C:2]1[C:3](=[O:30])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH3:33])[CH2:24][CH2:23]2)[CH:11]=1
Reactant: COc1ccc(CNc2cn[nH]c(=O)c2Cl)cc1OCCCN1CCN(C=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCBr
Solvent: O
Solvent: CCO
Product: CCN1CCN(CCCOc2cc(CNc3cn[nH]c(=O)c3Cl)ccc2OC)CC1
Reaction time: 3.5 h
Yield: 50 %

Procedure:
A mixture comprising 1.0 g of 4-chloro-5-[3-{3-(4-formylpiperazin-1-yl)-propoxy}-4-methoxybenzylamino]-3(2H)-pyridazinone, 0.62 g of potassium hydroxide, 7 ml of ethanol and 7 ml of water, was refluxed under heating with stirring for 3.5 hours, and then 0.32 g of potassium carbonate and 570 mg of ethyl bromide were added thereto. The mixture was stirred at 60° C. for 4 hours. The solvent was distilled off under reduced pressure, and water was added to the obtained residue. The mixture was extracted with chloroform. The extract solution was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 0.50 g of the above-identified compound as slightly brown solid.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C[O-].[Na+].Cl[C:8]1[CH:9]=[C:10]([C:15]#[N:16])[CH:11]=[N:12][C:13]=1[Cl:14]>CO>[Cl:1][C:8]1[CH:9]=[C:10]([C:15](=[NH:16])[NH:2][OH:3])[CH:11]=[N:12][C:13]=1[Cl:14]
Reactant: Cl
Reactant: N#Cc1cnc(Cl)c(Cl)c1
Reactant: NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cnc(Cl)c(Cl)c1
Yield: 81.5 %

Procedure:
Hydroxylamine hydrochloride (2.6 g, 0.038 mol) was slurried in methanol (75 mL) and sodium methoxide (2.0 g, 0.037 mol) added. The mixture was stirred for half an hour and 5,6-dichloro-3-pyridinecarbonitrile (4.3 g, 0.025 mol) added. The mixture was stirred at room temperature overnight and filtered. The precipitate was washed with water and methanol and dried to give the desired product (4.2 g, 82%) as a white solid, MP 182-184° C.