Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14].[C:15]([CH2:17][CH2:18][C@H:19]([CH2:23][C:24]([O-:26])=[O:25])[C:20]([O-:22])=[O:21])#[N:16].CO>O=[Pt]=O.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][O:4][C:3]1=[O:14].[NH2:16][CH2:15][CH2:17][CH2:18][C@H:19]([CH2:23][C:24]([O-:26])=[O:25])[C:20]([O-:22])=[O:21]
Reactant: N#CCC[C@H](CC(=O)[O-])C(=O)[O-]
Agent: O=[Pt]=O
Agent: CN1C(=O)OC[C@H]1Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCC[C@H](CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 71 (2.0 g, 5.8 mmol), PtO2 (0.8 g), CH3OH (50 mL), and CHCl3 (5 mL) were shaken on the Parr apparatus under a hydrogen atmosphere (60 PSI) at ambient temperature for 3 hours. The reaction mixture was filtered through a celite pad and then concentrated to furnish the crude amine HCl 72 as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12]O)=[O:6])#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:47][S:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:55][C:52]1[CH:53]=[CH:54][C:49]([S:48][CH3:47])=[CH:50][CH:51]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCC[C@H]1CO
Reactant: CSc1ccc(S)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(SC[C@@H]2CCC[C@H]2C(=O)NCC#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
trans-N-(Cyanomethyl)-2-(hydroxymethyl)cyclopentane carboxamide (11 mg, 63 mmol) and triphenylphosphine (19 mg, 72 mmol) were placed in a 1 mL vial and dimethylformamide (0.15 mL) was added. The reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (14 μL, 69 μmol) was added. After stirring for 10 min., 4-(methylsulfanyl)thiophenol (11 μL, 72 μmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and 1:1 water:saturated aqueous sodium chloride (10 mL). The product was extracted into ethyl acetate. The combined organic phase was dried with anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on silica gel eluting with 2:3 ethyl acetate:hexanes provided the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.75 (1H, br s), 7.29 (2H, d), 7.21 (2H, d), 4.21 (2H, d), 3.10 (1H, dd), 2.89 (1H, dd), 2.51 (1H, q), 2.46 (3H, s), 2.43 (1H, m), 1.99-1.90 (2H, m), 1.75 (1H, m), 1.70-1.61 (2H, m), 1.40 (1H, m). MS [ESI, (M−H)−] m/z=319.2 amu
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=O)OCCCl.[OH-].[K+].[C:20](O)(=[O:22])C>O>[OH:22][CH2:20][CH2:12][NH:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: CC(=O)O
Reactant: Cc1c(NC(=O)OCCCl)cccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(NCCO)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
25.8 g of the β-chloroethyl N-(2-methyl-3-nitrophenyl)-carbamate prepared under Example 3, stage 1, are initially introduced into the reaction vessel in 250 ml of water. The reaction mixture is heated to 80° C. and 35 g of 50% strength aqueous potassium hydroxide solution are then added in the course of one hour. After the mixture has been subsequently stirred at 75° C. for 3 hours, its pH is brought to 8 with glacial acetic acid, and the reaction mixture is cooled slowly. The product which has precipitated is filtered off with suction, washed with water, and dried at 50° C. in a vacuum drying cabinet.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](=[O:13])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[C:10]([F:11])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:13])=[O:14]
Reactant: [OH-]
Reactant: O=C1Nc2c(ccc(F)c2F)C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1c(C(=O)O)ccc(F)c1F
Temperature: 65 °C

Procedure:
6,7-Difluoroisatin (22.2 g) was added to a solution of sodium hydroxide (2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was added at 40° C. or less over 20 minutes. After 1 hour the mixture was heated to 65° C. for 0.5 hours, cooled, poured onto water and acidified with concentrated hydrochloric acid. The resulting solid was filtered, washed with water and recrystallized from ethyl acetate/cyclohexane to give 2-amino-3,4-difluorobenzoic acid (1.3 g) as an orange solid, m.p. 207-208° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (679 mg, 1.69 mmol) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.498 mL, 1.69 mmol) dissolved in water (0.800 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.104 mL, 1.69 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8.71 mL, 52.27 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (311 mg, 50%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: COc1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-methoxyphenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)=[C:16]([CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[C:1]([O:5][C:6](=[O:28])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:22][CH:21]=2)=[C:16]([CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(CN(CCC(C)C)C(=O)OC(C)(C)C)ccc1-c1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(4′-Amino-2-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester, (I-9b: 128 mg, 0.335 mmol) was dissolved in 7 ml of dichloromethane and treated with triethylamine (0.188 mL, 1.34 mmol) and methylsulfonyl chloride (0.077 mL, 1.0 mmol). After 12 hours, the volatiles were removed under reduced pressure and the residue was then dissolved in methanol (15 mL) and treated with a 2N sodium hydroxide solution (15 mL). After stirring at 50° C. for 1 hour, the reaction mixture was then concentrated under reduced pressure and residue dissolved in ethyl acetate and extracted with water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography eluting with 65% ethyl acetate in heptane to afford the title compound (I-8c).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4](=[O:10])[CH2:3]1.[Br:12]Br>C(O)(=O)C>[Br:12][CH:5]1[C:4](=[O:10])[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:8][NH:7][C:6]1=[O:9]
Reactant: BrBr
Reactant: CC1(C)CNC(=O)CC(=O)C1
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)C(Br)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.5 %

Procedure:
To a solution of 6,6-dimethylazepan-2,4-dione (10.0 g, 64.5 mmol) in glacial acetic acid (160 mL) was added bromine (3.3 mL, 64.5 mmol) dropwise. The reaction mixture was stirred at r.t. for 1 h. The resulting precipitate was collected by filtration to give the title compound (16.83 g, quantitative) as a white solid. δH (DMSO-d6) 0.86 (3H, s), 0.99 (3H, s), 2.31 (1H, d, J 11.7 Hz), 2.73 (1H, d, J 11.7 Hz), 2.75 (1H, dd, J 15.2, 6.6 Hz), 3.31 (1H, dd, J 15.2, 6.6 Hz), 5.77 (1H, s), 8.40 (1H, t, J 6.2 Hz). LCMS (ES+) 234/236 (M+H)+.
Reaction SMILES: [NH4+].[N:2]([C@H:5]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4].[N:18]([C@H]1[C@H](O)[C@H](O)[C@@H](CO)[O:23]C1)=[N+]=[N-]>>[NH4+:2].[NH4+:18].[N:2]([C@H:5]1[C@H:10]([OH:23])[C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](CO)[C@@H](O)[C@H]1O
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)C1
Agent: [NH4+]
Product: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Phosphate 12 is prepared similarly to phosphate 5 starting from azide 11 (0.503 g. 2.66 mmol). Coarse purification by column chromatography and silica gel (0.35% ammonia (20% aqueous solution in i-PrOH) pale yellow oil 12 (0.353 g, 46%). Rf 0.4 (i-PrOH/25%-NH4OHaq/H2O 6/4/1). This product is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 96.3 %

Procedure:
A mixture of 3'-(2,4-difluorophenylthio)-4'-nitroacetophenone (2.3 g), iron powder (2 g), and ammonium chloride (0.2 g) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated to give crystals of 4'-amino-3'-(2,4-difluorophenylthio)acetophenone (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:16][O:17][C:18]1[C:19](=[O:24])[CH:20]=[CH:21]/[C:22](=[N:1]\[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:23]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: COc1ccccc1O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COC1=C/C(=N/c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 2-methoxyphenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16].O>CN(C)C=O>[C:2](=[N:4][O:5][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16])([CH3:3])[CH3:1]
Reactant: COCOc1cccc(F)c1C#N
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc(ON=C(C)C)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Acetone oxime (11.14 g, 0.1524 mole) was dissolved in 300 ml of dry dimethyl formamide (DMF) and then potassium t-butoxide (17.0 g, 0.152 mole) was added portionwise. The reaction mixture was allowed to stir for 30 minutes at room temperature and the 2-fluoro-6-methoxymethoxybenzonitrile of Example 1(b) (23.0 g, 0.127 mole) was added in 150 ml of DMF. After 30 minutes the reaction mixture was poured into 1000 ml of water and stirred well as the product crystallized. The product was filtered off, washed well with water, and then taken up in CH2Cl2 and dried with magnesium sulfate. Concentration and recrystallization from methanol-water gave 20.5 g (69%) of 2-[(isopropylideneamino)oxy]-6-methoxymethoxybenzonitrile as fine needles, mp 62°-64° C.
Reaction SMILES: C1C=CC(CC(NC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=O)=CC=1.[CH3:23][C:24]1([CH3:46])[S:28][C@@H:27]2[C@H:29]([NH:32]C(COC3C=CC=CC=3)=O)[C:30](=[O:31])[N:26]2[C@H:25]1[C:43]([O-:45])=[O:44].[K+].O>C(N(CC)CC)C>[CH3:23][C:24]1([CH3:46])[S:28][C@@H:27]2[C@H:29]([NH2:32])[C:30](=[O:31])[N:26]2[C@H:25]1[C:43]([OH:45])=[O:44]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C(Cc1ccccc1)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 38 °C
Reaction time: 9 h
Yield: 83.7 %

Procedure:
290 g of carrier-bound penicillinacylase according to Example 4, having an enzymatic activity of 2,803 U (NIPAB test) and 138 g of potassium penicillin V are added to 2,000 ml of water and stirred for 9 hours at 38°C. The pH value is kept constant at 7.8 by continuous addition of triethylamine. The mixture is worked up as described in Example 1. Yields of 6-APA 64.3 g (86.1% of theory); purity 97.4%.
Reaction SMILES: Cl.C([O:4]C(=O)[C@H](CC1C=CC=CC=1)N)C.[CH:16]([N:19]=[C:20]=[N:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>O>[CH:16]([NH:19][C:20](=[O:4])[NH:21][CH:22]([CH3:24])[CH3:23])([CH3:18])[CH3:17]
Reactant: CC(C)N=C=NC(C)C
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)NC(C)C
Reaction time: 20 h

Procedure:
Then 11.5 g (50 mM) of Phenylalanine Ethyl Ester hydrochloride and 7.75 mL (45 mM) of diisopropylcarbodiimide were added. Then 8.6 mL (50 mM) of diisopropylethylamine was added via the dropping funnel for 10 min. The reaction mixture was kept for 20 hours at a room temperature, then 10 mL of H2O was added, a precipitate of diisopropylurea formed was filtered off, a resulted solution was analyzed by HPLC. According analysis, the reaction was completed at 50%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19])=[O:14]>O1CCCC1>[CH3:8][O:9][CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH:18]=[O:19])=[O:14]
Reactant: COCCN
Reactant: O=Cc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a mixture of 200 ml of tetrahydrofuran, 16.70 g of triethylamine and 12.40 g of 2-methoxyethylamine was added a solution of 16.00 g of 3-formylbenzoic acid chloride in 20 ml of tetrahydrofuran at room temperature. After stirred at room temperature for 6 hours, insolubles were filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 10.79 g of oily 3-[(2-methoxyethyl)aminocarbonyl]benzaldehyde [Compound No. (d)].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[H-].[Na+].I[CH3:30].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:30])=[CH:4][C:3]=1[CH2:11][C:12]1[N:16]2[N:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1
Reactant: CI
Reactant: Cn1cc(-c2ccc3ncc(Cc4cc5cn[nH]c5cc4F)n3n2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4cc5cnn(C)c5cc4F)n3n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(6-Fluoro-1H-indazol-5-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 167, 18.6 mg, 0.054 mmol) was dissolved in DMF (0.310 mL) and cooled down to 0° C. NaH (1.9 mg, 0.080 mmol) was added and the RM was stirred for 30 min. Then iodomethane (4.02 μL) was introduced and it was allowed to warm up to rt. After 2.5 h of stirring, water was added and it was extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and were lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt of the title compound as a white solid (tR 1.0 min (conditions 2), MH+=362).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Sc2ccccc2CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Sc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenylthio)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of saturated sodium chloride solution and dried, providing 2-(4-fluorophenylthio)benzyl cyanide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[OH-:18].[Na+]>C(O)C>[CH3:4][C:5]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]2[C:8](=[O:18])[C:6]=1[CH2:7][CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)c1ccnc(N)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1ccn2c(=O)c(CC)c(C)nc2c1
Yield: 42 %

Procedure:
0.02 moles of 2-amino-4-ethoxycarbonylpyridine and 0.02 moles of ethyl-2-ethylacetacetate are stirred in a mixture of 10 ml. of phosphorous oxychloride and 2 g. of polyphosphoric acid at 120° C. for 2 hours. The reaction mixture is treated with 20 ml. of ethanol at 70° to 80° C., whereupon it is neutralized with a 10% (w/v) aqueous sodium hydroxide solution with ice cooling. The ethanol is evaporated, the residue is extracted with four 25-ml. portions of chloroform and the combined extracts are dried and evaporated. The evaporation residue is triturated with ether to give crystalline 2-methyl-3-ethyl-8-ethoxycarbonyl-4-oxo-4H-pyrido-(1,2-a)pyrimidine, melting at 95° to 96° C. Yield 42%. The product does not give any melting point depression when admixed with the product of Example 17.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[F:44][C:45]([F:56])([F:55])[CH2:46][O:47][C:48]1[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:54][C:51]3[CH:52]=[N:53][C:48]([O:47][CH2:46][C:45]([F:44])([F:55])[F:56])=[CH:49][CH:50]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(OCC(F)(F)F)nc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine according to procedure B followed by deprotection yielded the title compound as an off-white foam. MS (ESI): m/z=454.2 [M+H]+.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C([Cl:9])=O.O[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1>ClCCCl>[Cl:9][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][C:24](=[O:26])[CH3:25])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(O)c2cc1OC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
To a stirred solution of anhydrous DMF (4.5 mL) in DCE (20 mL), cooled in an ice-water bath, is added dropwise under nitrogen a solution of oxalyl chloride (7.9 ml, 90 mmol) in DCE (40 mL). A white precipitate forms during the addition. After the end of addition the cold bath is removed and the reaction mixture is stirred at room temperature for 5 min. Acetic acid 4-hydroxy-7-methoxy-quinazolin-6-yl ester (6.5 g, 27.8 mmol) is added in portions via scoopula under nitrogen flow and the mixture is heated immediately to reflux. Heating is continued for 3 hours, followed by cooling to room temperature. The reaction mixture is poured into excess ice:water mixture (100 mL) and extracted with DCM (500 mL). The aqueous layer is further extracted with DCM (2×50 mL). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to yield 5.63 g (22.34 mmol, 80%) of desired product as a tan solid.