Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]=O.[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:11]1[C:10]2[C:14](=[CH:15][C:7]([F:6])=[CH:8][CH:9]=2)[NH:13][CH:12]=1)[CH3:3]
Reactant: C=O
Reactant: CNC
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)Cc1c[nH]c2cc(F)ccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Add dropwise 422 mL of glacial acetic acid to 40% aqueous dimethylamine (408 mL) over 40 minutes while maintaining the temperature below about 15° C. Cool to 0° C. After stirring for 20 minutes at 0° C., slowly add 37% aqueous formaldehyde (289 mL, 1.3 eq.) over about 15 minutes. Add 6-fluoroindole (400 g, 2.96 mol, 1 eq.) in four portions over about 15 minutes. After 30 minutes, divide the reaction mixture into two portions. To one portion, slowly 1149 g (75% of total mass) over 30 minutes to 3 L of 10% NaOH and stir at room temperature. After 18 hours, collect the solid that forms, wash three times with 200 mL of water, dry by suction to give wet 3-(N,N-dimethylaminomethyl)-6-fluoroindole.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: COc1ccc(C)cc1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol), 2-methoxy-5-methylbenzoic acid (CAS number 25045-36-7; 53 mg, 0.32 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (61 mg, 0.40 mmol), EDC (76 mg, 0.40 mmol) and triethylamine (111 μl, 0.80 mmol) in dry DCM (1 ml) was stirred at room temperature for 24 hours. The reaction mixture was partitioned between DCM (3 ml) and water (2 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][N:16]=[C:15]2[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([CH3:11])[NH:10][C:6]=2[CH:5]=1
Reactant: Cc1nc2ccc(O)cc2[nH]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4nc(C)[nH]c4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
Sodium hydride (71 mg, 1.8 mmol) was added to 5-hydroxy-2-methylbenzimidazole (204 mg, 0.89 mmol) in anhydrous DMF (2.5 ml) under an argon atmosphere. The mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) was added and the reaction mixture stirred at 95° C. for 2 hours. Upon cooling to ambient temperature the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), silica was added and the solvent evaporated off. The obtained powder was placed on the top of a disposable silica column (ISOLUTE) and the product eluted off using a gradient of methanol/dichloromethane (3/97, 5/95, 8/92). Evaporation of the solvent gave 6,7-dimethoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)quinazoline (145 mg, 48%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[N:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>O1CCCC1.N1C=CC=CC=1>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:27]([C:33]#[N:34])=[CH:28][N:29]=[C:30]3[C:25]=2[CH:24]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:32]=[N:31]3)[CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CC#CC(=O)Nc1cnc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.8 %

Procedure:
To a solution of 0.85 g (10.1 mmol) of tetrolic acid and 1.8 g (17.96 mmol) of N-methyl morpholine in 18 ml of tetrahydrofuran was stirred at 0° C. as 1.35 g (9.9 mmol) of isobutyl chloroformate was slowly added. After 15 min, this mixture was added to a solution of 1.3 g (3.8 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 5 mg of 4-N,N-dimethylamino-pyridine in 10 ml pyridine. The mixture was stirred a room temperature for 2.25 hr. The tetrahydrofuran was removed, diluted sodium bicarbonate was added, and the solid was collected via filtration. The solid was air dried and chromatographed on silica gel eluting with ethyl acetate-methanol mixtures giving 0.46 g of the title compound as a tan powder: mass spectrum (electrospray, m/e): M+H 408.1, 406.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>ClCCl.N1C=CC=CC=1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)O1
Reactant: COCCOCOc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COCCOCOc1ccc(NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
To a solution of 510 mg (2.58 mmol) of 4-[(2-methoxyethoxy) methoxy]benzenamine (22) in 8 mL of dichloromethane and 2 mL of anhydrous pyridine (Aldrich) was added 380 mg (3.8 mmol) of succinic anhydride portionwise. The mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 20 mL of methanol and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative thin layer chromatography using 8:2 chloroform:methanol as an eluent to yield 420 mg (1.41 mmol, 55%) of 4-[[4-[(2-methoxyethoxy)methoxy]phenyl]amino]-4-oxobutanoic acid (23). NMR, IR and MS data confirmed the compound identity.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][CH:29]([CH3:33])[C:30](Cl)=[O:31]>C1COCC1>[CH3:28][CH:29]([CH3:33])[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1)=[O:31].[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)(=[O:31])[CH:29]([CH3:33])[CH3:28]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (8.20 g, 29.7 mmol) and triethylamine (8.4 mL, 60 mmol) in dry THF (100 mL) at 0° C. was slowly added a solution of 2-methylpropanoyl chloride (3.84 g, 36.0 mmol) in THF (50 mL). The reaction mixture was then warmed up to room temperature and stirred for 2 h. After removing the solvent in vacuo, the crude product was purified by recrystallization (hexane/THF), affording the desired amide, tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate, as a white solid (8.60 g, 84%). The tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate was dissolved in CH2Cl2 (50 mL) at room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was added by syringe. The reaction mixture was stirred for 3 or 4 h and another 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 more hours. The reaction solution was then basified to pH>14 by KOH (aq, 2 M). The solution was extracted with CH2Cl2 (8×200 mL). The combined organic layer was dried over K2CO3. Removal of solvent under reduced pressure gave the free amine, 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide, as a brownish solid (5.99 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.55–7.35 (m, 2H), 7.35–6.9 (m, 3H), 3.26–2.98 (m, 2H), 2.84–2.64 (m, 2H), 2.64–2.53 (m, 1H), 2.53–2.32 (m, 1H), 1.90–1.68 (m, 2H), 1.68–1.36 (m, 3H), 1.22 (d, 6H, J=6.0 Hz); ESMS m/e: 247.1 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#[N:2].F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[C:1]([CH2:3][C:4]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:19]=1)#[N:2]
Reactant: N#CCC(N)=O
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-Cyanoacetamide (120 mg, 1.5 mmol) and triethyloxonium tetrafluoroborate (270 mg, 1.4 mmol) in THF (1.1 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.5 mL) and added to a suspension of tert-butyl ({trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl)carbamate (150 mg, 0.40 mmol) in ethanol (1.7 mL). The mixture was stirred at 85° C. for 2 h. The solid was filtered and the filtrate was concentrated and purified on flash chromatography (0-10% methanol/dichloromethane) to give the desired product (0.12 g, 71%). LCMS calculated for C22H28N5O2S (M+H)+: m/z=426.2. Found: 426.0.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10].[CH2:18]([O:20][C:21]#[CH:22])[CH3:19]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]1[C:11]([CH2:15][CH2:16][CH3:17])([CH2:8][CH2:9][CH3:10])[C:12](=[O:13])[CH:19]=1)[CH3:22]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: C#COCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C=C1OCC
Reaction time: 48 h
Yield: 66.6 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (29 ml) was added dropwise at room temperature to a well-stirred solution of di-n-propylacetyl chloride (13.9 g, 85.8 mmol) and ethyl ethynylether (15 g, 40% solution in hexanes, 85.7 mmol) in toluene (120 ml. The reaction was warmed to 60° and stirred for 48 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a brown oil (11.2 g, 57.1 mmol, 67%). δH (CDCl3, 300K) 5.02 (1H, s), 4.32 (2H, q, J 7.1 Hz), 1.69-1.61 (4H, m), 1.45-1.40 (4H, m), 1.02 (6H, t, J 7.3 Hz). m/z (ES+, 70V) 197.1 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>>[CH3:1][N:2]1[C:6]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])cn1
Reactant: O=C1CCC2(CC1)OCCO2
Product: Cn1ncc([N+](=O)[O-])c1C1(O)CCC2(CC1)OCCO2
Yield: 83 %

Procedure:
Following the procedure for Intermediate 218 starting from 1-methyl-4-nitro-1H-pyrazole and 1,4-cyclohexanedione monoethylene acetal gave 8-(2-methyl-4-nitro-pyrazol-3-yl)-1,4-dioxaspiro[4.5]decan-8-ol as a light beige solid (3.68 g, 83%). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 4.45 (s, 1H), 4.12 (s, 3H), 4.04-3.93 (m, 4H), 2.44-2.34 (m, 2H), 2.23-1.95 (m, 4H), 1.75-1.67 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3=[N:10][C:11]([C:20]4[CH:24]=[C:23]([CH3:25])[S:22][C:21]=4[CH3:26])=[C:12]([CH:13](O)[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[N:7]3[C:6]=2[CH:27]=1.S(Cl)([Cl:30])=O.CN(C)C=O>ClCCl>[ClH:1].[Cl:30][CH:13]([C:12]1[N:7]2[C:8]([S:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][C:6]=32)=[N:10][C:11]=1[C:20]1[CH:24]=[C:23]([CH3:25])[S:22][C:21]=1[CH3:26])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: Cc1cc(-c2nc3sc4ccc(Cl)cc4n3c2C(O)C(=O)N(C)C)c(C)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3sc4ccc(Cl)cc4n3c2C(Cl)C(=O)N(C)C)c(C)s1
Product: Cl
Yield: 205.2 %

Procedure:
18 g (0.0431 mole) of 6-chloro-α-hydroxy-N,N-dimethyl-2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetamide are treated with 31 ml (0.43 mole) of thionyl chloride, 2 ml of N,N-dimethyl formamide and 100 ml of dichloromethane at the reflux temperature for 6 h. The solvent and the excess thionyl chloride are removed under reduced pressure, the residue is taken up in diethyl ether, the solid is washed with diethyl ether and it is dried. 21 g of α,6-dichloro-N,N-dimethyl-2-(2,5-dimethylthien-3-yl)imidazo[2,1-b]benzothiazole-3-acetamide hydrochloride are obtained which are reduced with 21 g (0.136 mole) of Rongalite® in 300 ml of dichloromethane at room temperature for 24 h. The solution is separated after settling has taken place, the solid is washed with dichloromethane, the organic phase is washed with a saturated sodium hydrogen carbonate solution and then with water, it is dried over sodium sulphate and the solvent is evaporated under reduced pressure. An oil is obtained which crystallizes and which is recrystallized from acetonitrile. 14.4 g of yellow needles are finally isolated. Melting point: 202°-203° C.
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:4].[H-].[Na+].[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34]CCCCC>O1CCCC1>[C:11]([OH:13])(=[O:12])[CH2:10][CH2:3][CH2:2][CH2:1][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[C:11]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][C:3]([CH2:2][C:1]([O:17][CH2:18][CH3:19])=[O:16])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:4]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Agent: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of triethyl citrate (0.87 g, 1 equivalent) in tetrahydrofuran (THF) was added to a solution of sodium hydride (0.2 g, 1.5 equivalents) in THF at 0° C. and stirred at 0° C. for 1 hour. Then oleoyl chloride (0.87 g, 1 equivalent) was added and stirred for 1 hour at 0° C. under nitrogen atmosphere. The mixture was stirred at 25-30° C. for 8 hours. Thin layer chromatography analysis indicated that the reaction was complete. The mixture was quenched with cold water and extracted with ethyl acetate. The ethyl acetate phase was washed with sodium bicarbonate solution (10%) followed by water and then brine solution. The resulting mixture was dried over sodium sulphate and concentrated to obtain a crude product. Purified product was obtained from the crude product by column chromatography using 10% petroleum ether in ethyl acetate as eluent. Yield of product was 0.6 g.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-4-trifluoromethylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])#[N:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]([CH3:41])([CH3:40])[C:37]([N:6]1[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:38])#[N:35]
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Reactant: CC(C)(C#N)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)C(C)(C)C#N)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (30 mg, 0.042 mmol), 2-cyano-2-methylpropanoic acid (14.39 mg, 0.127 mmol), BOP (56.3 mg, 0.127 mmol) and Hunig's Base (0.052 mL, 0.297 mmol) in DMF (0.25 mL) was stirred at rt for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 26% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.79 (dd, J=9.4, 2.0 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06-7.93 (m, 2H), 7.38 (dd, J=8.2, 3.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.07-4.87 (m, 1H), 4.57 (s, 2H), 4.36-4.14 (m, 2H), 3.97 (s, 2H), 3.95-3.68 (m, 2H), 3.46 (s, 3H), 2.68-2.44 (m, 1H), 1.83-1.39 (m, 8H), 1.07-0.95 (m, 3H). MS (ES+) m/z: 547.1 (M+H); LC retention time: 1.19 min (analytical LCMS Method H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5](NC(CNC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CC1C=CC(O)=CC=1)=O)CC(N)=O)=O)CC1C2C(=CC=CC=2)NC=1)=O)CC(N)=O)=O)CO)=O)CC1C=CC=CC=1)=O)=O)C(N[C@H](C(N[C@H](C(N)=O)CC1C=CC=CC=1)=O)CCCN=C(N)N)=O)[CH3:3].[CH:95]([O:102][CH2:103][CH3:104])([O:99]CC)OCC.CC(C)=CC=O>C(O)CO>[CH3:1][C:2]([CH3:3])=[CH:4][CH3:5].[O:102]1[CH2:103][CH2:104][O:99][CH2:95]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: CC(C)=CC=O
Solvent: OCCO
Product: C1COCO1
Product: CC=C(C)C
Temperature: 4 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
0.5 undried catalyst KP-10 (Sud-Chemie), 79.6 g triethyl orthoformate and 48.2 g 3-methyl-crotonaldehyde were placed in a flask in a nitrogen atmosphere in 34.3 g ethyleneglycol and stirred at 4° C. for 1.5 hours. Then the catalyst was filtered off through a suction filter and washed with 20 ml ethanol. The product was concentrated and isolated by fractionated distillation (2 fractions at 204 mbar/107° C). The 3-methyl-2-butene-1,3-dioxolane fractions obtained had a content of 81% (39.2 g) and 86.9% (3 g) (47% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[NH:11][C:12](=[O:28])[N:13]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:14]=1)#[N:9]>ClCCl>[O:28]=[C:12]1[NH:11][C:10]([C:8]#[N:9])=[CH:14][N:13]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cn(C2CCNCC2)c(=O)[nH]1
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-(4-cyano-2-oxo-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate (25 mg, 0.086 mmol) in dichloromethane (6 mL). After 20 min, the reaction was concentrated to give the title compound. MS 193.3 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]1[C:19]([CH2:20][O:21][Si](C(C)(C)C)(C)C)=[C:18]([Cl:29])[CH:17]=[CH:16][N:15]=1.[C:31](O)(=[O:33])[CH3:32]>>[C:31]([O:21][CH2:20][C:19]1[C:14]([C:13]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[N:15][CH:16]=[CH:17][C:18]=1[Cl:29])(=[O:33])[CH3:32]
Reactant: CC(C)(C)c1ccc(NC(=O)c2nccc(Cl)c2CO[Si](C)(C)C(C)(C)C)c(N)c1
Reactant: CC(=O)O
Product: CC(=O)OCc1c(Cl)ccnc1-c1nc2ccc(C(C)(C)C)cc2[nH]1
Yield: 44 %

Procedure:
A solution of 160g (10 g, 22 mmol) in acetic acid (100 mL) was stirred at 120° C. for 5 h. See FIG. 5. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=3:1) to afford (2-(6-(tert-butyl)-1H-benzo[d]imidazol-2-yl)-4-chloropyridin-3-yl)methyl acetate 160h (3.5 g, 44%) as a yellow solid. MS-ESI: [M+H]+ 358.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH3-][C:17]#N.[Na+].[CH3:20][C:21](O)=O>CO>[CH:21]1([N:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:17]1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(C2CCN(C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
4-(4-Nitrophenyl)piperidine (1.00 g, 4.85 mmol) was dissolved in 80 mL MeOH and 2 mL HOAc. To it was added (1-ethoxycycloproxy)trimethylsilane, and the mixture was stirred at RT for 40 min To it was then added NaBH3CN (1.83 g, 29.0 mmol), and the mixture was stirred in 65° C. bath for overnight. It was concentrated in vacuo to dryness, diluted with 120 mL EtOAc, washed with 1N NaOH and water ×2, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOh in DCM to isolate 1-cyclopropyl-4-(4-nitrophenyl)piperidine (256). It was dissolved in 50 mL EtOAc. To it was added 10% Pd/C (0.5 g), and the mixture was hydrogenated using a H2 balloon at RT for overnight. The mixture was filtered through celite, and concentrated in vacuo to give 4-(1-cyclopropylpiperidin-4-yl)aniline (257) (960 mg, 91% overall) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH3:24]I>>[CH3:24][N:14]1[C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[N:19][C:11]=2[S:10][C:9]1=[N:8][C:7]1[CH:20]=[CH:21][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc([N+](=O)[O-])cc2)sc2ncccc2c1=O
Yield: 80.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 511 mg of methyl iodide were used. The resulting residue was then purified through silica gel chromatography (eluant: chloroform) to obtain 756 mg of 2,3-dihydro-3-methyl-2-[(4-nitrophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (80%, recrystallized from a mixture of ether and ethanol).