Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].CO.[CH3:16][C:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:16][C:17]1([CH2:23][NH:1][C@@H:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C=O)CCCCC1
Reactant: COC(=O)c1ccc([C@@H](C)N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@@H](C)NCC2(C)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of (R)-methyl 4-(1-aminoethyl)benzoate (0.12 g, 0.67 mmol) in methanol (2.97 mL, 73.33 mmol) was added 1-methylcyclohexane-1-carboxaldehyde (0.093 g, 0.74 mmol) and acetic acid (0.152 mL, 2.67 mmol). The reaction was stirred for 1 hour at room temperature whereupon sodium cyanoborohydride (63.1 mg, 1.00 mmol) was added and the mixture further stirred at room temperature overnight. The solvent was evaporated and the residual sodium cyanoborohydride quenched with saturated aqueous NaHCO3. The mixture was extracted into ethyl acetate, the organic layer washed with brine and the solvent evaporated to dryness. The residue obtained was purified via silica chromatography (0-5% MeOH/DCM) to afford the title compound as a colorless oil (123.0 mg, 63%). LC-MS: (FA) ES+ 290.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([Cl:23])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([CH:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:8]2=[O:20])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:22]=[C:21]([Cl:23])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[C:8]1=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC1CCC(C2CCN(Cc3c(Cl)cc(Br)cc3Cl)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Temperature: 80 °C
Yield: 108.6 %

Procedure:
A mixture of 1-(4-Bromo-2,6-dichloro-benzyl)-3-(4-methoxy-cyclohexyl)-pyrrolidin-2-one (0.4 g, 0.92 mmol) and 4-fluorophenylboronic acid (0.19 g, 1.38 mmol) in THF (15 mL) and water (5 mL) and sodium carbonate (0.29, 0.75 g) is purged with N2. Treat the reaction with Pd(PPh3)4 (0.05 g, 0.046 mmol) and heat to 80° C. for 2 hour under N2. Cool the reaction, dilute with ethyl acetate, and wash with HCl (1N) and water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 35% ethyl acetate in hexanes to afford 0.45 g of the titled product. MS (m/z): 451 (M+).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CCO>[F:9][CH:8]([F:10])[CH2:7][N:6]1[C:2]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16][CH2:15]2)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]1
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Reactant: OC1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1cnn(CC(F)F)c1N1CCCC(O)CC1
Yield: 62.1 %

Procedure:
A solution of 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole (470 mg, 2.22 mmol), azepan-4-ol (281 mg, 2.44 mmol) and DIPEA (1 mL) in EtOH (3 mL) was heated at 155° C. in the microwave for 5 hr. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0-100% EtOAc/isohexane) to give 1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a pale orange gum (400 mg). This gum (390 mg, 1.35 mmol) was dissolved in MeOH (25 mL) and treated with ammonium formate (340 mg, 5.38 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 85° C. for 4 hr. After standing at room temperature overnight more ammonium formate (205 mg, 3.25 mmol) and 10% palladium on carbon (50 mg) were added to the reaction mixture which was then heated at 85° C. for 1 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between DCM (30 mL) and water (20 mL). The organic layer was passed through a phase separation cartridge and the solvent was removed under reduced pressure to afford 1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)azepan-4-ol as an orange oil (265 mg, 42% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.27-5.91 (m, 1H), 4.39-4.23 (m, 2H), 4.16-4.04 (m, 1H), 3.30-3.11 (m, 4H), 2.60 (br s, 3H), 2.55 (s, 2H), 2.08-1.81 (m, 3H), 1.80-1.71 (m, 1H).
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=C[C:3]=1[NH2:4].BrN1C(=O)CC[C:12]1=O.O.[CH2:19]([NH2:22])[CH2:20]N>ClCCl>[C:3]([C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:20]([CH3:12])[C:19]=1[NH2:22])#[N:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Reactant: NCCN
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(N)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 2,4-dimethylaniline (9.80 g, 80.9 mmol) in dichloromethane (200 mL) at 0° C. was added N-bromosuccinimide (15.1 g, 84.9 mmol) slowly. The mixture was allowed to warmed to room temperature and stirred at room temperature overnight before it was washed with 1 N NaOH. The organic layer was worked up and concentrated as usual. The residue was dissolved in N,N-dimethylformamide (120 mL) followed by the addition of cuprous cyanide (14.5 g, 161.8 mmol). The mixture was heated under reflux for 8 h and then allowed to cool to rt and poured into water (1 L). The mixture was treated with excess ethylenediamine and the precipitate was filtered, redissolved in ethyl acetate, dried with MgSO4 and then concentrated to give the desired compound as an oil (6.7 g, 55%).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][S:8]([O-:10])=[O:9].[Na+].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20](I)[CH:21]=1)[C:16]([O-:18])=[O:17].[CH3:23]NCCNC>C(OCC)(=O)C.CS(C)=O>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([S:8]([CH3:7])(=[O:10])=[O:9])[CH:21]=1)[C:16]([O:18][CH3:23])=[O:17]
Reactant: O=C([O-])c1cc(Br)cc(I)c1
Reactant: CS(=O)[O-]
Reactant: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 440.9 %

Procedure:
To a sealable tube equipped with a stir bar were added (CuOTf)2.PhH (164 mg, 0.29 mmol), sodium methanesulfinate (847.8 mg, 7.06 mmol) and 3-bromo-5-iodobenzoate (2.0 g, 5.88 mmol). The tube was then covered with a rubber septa and a nitrogen atmosphere was established. N,N′-dimethylethylenediamine (54.6 mg, 0.07 mL, 0.588 mmol) and anhydrous DMSO (5.88 mL) were added via syringe and the septa was replaced by a Teflon-coated screw cap and the reaction vessel was placed in a 110° C. oil bath. After stirred for 20 h, the reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (60 mL) and filtered through a pad of silica gel. The filtrate was washed with H2O (100 mL) twice, brine (100 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude mixture was purified by reverse phase prep HPLC to give the title compound (760 mg): 1H NMR (CD3OD, 500 MHz) δ ppm 3.21 (3H, s), 3.99 (3H, s), 8.36 (1H, m), 8.46 (1H, m), 8.50 (1H, m). HPLC retention time: 1.578 min (method A). MS (ESI) (M+H)+ 292.00.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][O:16][C:15]([C:6]1[C:7]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1NCCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid (6.25 g) was dissolved into DMF (50 ml), to which then potassium carbonate (11 g) and methyl iodide (4.9 ml) were added, and was stirred for 2 hours at room temperature. After the insoluble matter was filtered off and the filtrate was concentrated, ethyl acetate (500 ml) was added to the residue, which was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to give the intended compound 6.65 g (quantitatively) as yellow crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:1]3[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]3)[N:27]=2)=[CH:18]1
Reactant: NC1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 71.8 %

Procedure:
Using the procedure of example 1, piperidin-4-ylamine (540 mg) was reacted with compound 1f (500 mg) to provide compound 62 (285 mg, 72%). 1H NMR (400MHz, DMSO) δ 8.70 (d, 1 H), 8.40 (s, 1 H), 8.25 (m, 1 H), 8.20 (d, 1 H), 7.20 (m, 1 H), 7.05 (d, 1 H), 4.60 (d, 2 H), 3.05 (m, 2 H), 2.85 (m, 1 H), 1.85 (m, 2 H), 1.25 (m, 2 H). MS (ESI) m/z: 295 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)#[N:2].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C>C(OCC)(=O)C.O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=4)=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2C#N)ccn1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)c4)c(C#N)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of acid 111-10 (150 mg crude from above containing about 25 mg, 0.1 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (22 mg, 0.1 mmol) 111-4, o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 40 mg, 0.105 mmol) were added DMF (1 mL) and diispropylethyl amine (DIEA, 38.7 mg, 0.3 mmol) and the mixture was stirred at room temperature overnight. Then it was redistributed between water (30 mL) and ethyl acetate (30 mL). The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The oily reside was subjected to both reverse phase preparative HPLC and silica gel chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-4-(2-methylpyridin-4-yl)phenyl)acetamide (Compound 111) as a white solid. MS m/z 455.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:33])[CH2:22][N:23]3[CH2:32][CH2:31][C:26]4(OCC[O:27]4)[CH2:25][CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1.CO.C(Cl)Cl>Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][CH:21]([OH:33])[CH2:22][N:23]3[CH2:32][CH2:31][C:26](=[O:27])[CH2:25][CH2:24]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC3(CC2)OCCO3)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC(=O)CC2)C1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A suspension of 0.50 g (0.96 mmol) of 1-{3-(4-chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone in 1 N HCl (2.0 mL) was heated to 65° C. for 48 h in a sealed vessel. The reaction was allowed to cool to room temperature and was diluted with CHCl3 (20 mL) and saturated NaHCO3 (20 mL). The aqueous phase was extracted with CHCl3 (2×10 mL) and the combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was then diluted with Ac2O (3.0 mL) and was stirred for 48 h. The solvent was removed under reduced pressure and the crude material was pumped down overnight. The resulting solid was dissolved in MeOH (5.0 mL) and a catalytic amount (0.05 g) of K2CO3 was added to the mixture and stirring was continued overnight. The reaction was then diluted with H2O (20 mL) and CH2Cl2 (20 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL) and the combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-10% MeOH/CH2Cl2) afforded 0.29 g (65% over 3 steps) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.35. MS (electrospray); m/z calculated for C22H27ClN4O3, [M+H]+, 431.18, observed 431.1. 1H NMR (400 MHz, CDCl3, a mixture of amide rotamers): 7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.85 and 4.73 (A and B of AB quartet, Jab=15.8 Hz, 1H), 4.62 (s, 1H), 4.26-4.12 (m, 2H), 4.09-3.68 (m, 4H), 3.49 (s, 1.5H), 3.28 (s, 1.5H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:20][CH3:21])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[C:22](OCC)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:20][CH2:21][C:33](=[O:35])[CH3:34])[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9]2)=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CCOC(C)=O
Reactant: CNC1(c2ccc(O)cc2)Sc2ccccc2N(C)C1=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)CNC1(c2ccc(OC(C)=O)cc2)Sc2ccccc2N(C)C1=O
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
To a stirred suspension of 3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-2-methylamino-3-oxo-2H-1,4-benzothiazine (3.0 g, compound No. 66) in acetic anhydride (14.3 ml), fused sodium acetate (3.3 g) is added. The mixture is stirred for 3.5 hours at 85° C. and then poured into a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution. The separated crystals are collected by filtration to give 3.3 g (85.7%) of the title compound.
Reaction SMILES: Cl.Cl[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[N:5][N:4]=1.[CH3:14][NH:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:16])[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[N:5][N:4]=1
Reactant: CC(C)c1nnc(Cl)n(C)c1=O
Reactant: CNC
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)c1nnc(N(C)C)n(C)c1=O
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
30.0 g (0.15 mole) of 3-chloro-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one hydrochloride are suspended in 60 ml of toluene. With gentle cooling, a solution of 20.4 g (0.45 mole) of dimethylamine in 80 ml of toluene is run into the above still just stirrable mixture at about 30° C. over 2 minutes. The cooling is removed and the reaction mixture exotherms to 50° C. The reaction is complete after stirring for 15 minutes. The mixture is thoroughly stirred in 50 ml of cold water and the organic phase is separated, dried over magnesium sulfate and evaporated to dryness, affording a pale beige-coloured, clear oil in quantitative yield. Distillation yields 21.4 g (72.8%) of 3-dimethylamino-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one as a clear, colourless oil with b.p. 135° C./0.04 mm.
Reaction SMILES: O[CH2:2][C:3]1[CH2:10][S:9][C@H:8]2[N:5]([C:6](=[O:20])[C@H:7]2[N:11]=[CH:12][C:13]2[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=2)[OH:15])[C:4]=1[C:21]([O:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[C:37]1([P:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[I:56]I.C(O)(C)C>CN(C)C=O.O1CCCC1>[I-:56].[CH:24]([O:23][C:21]([C:4]1[N:5]2[C@H:8]([S:9][CH2:10][C:3]=1[CH2:2][P+:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@H:7]([N:11]=[CH:12][C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15])[C:6]2=[O:20])=[O:22])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CO)CS[C@@H]2[C@H](N=Cc3ccccc3O)C(=O)N12
Reactant: II
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2[C@H](N=Cc3ccccc3O)C(=O)N12
Product: [I-]
Reaction time: 0.25 h

Procedure:
To a solution of benzhydryl (6R,7R)-3-hydroxymethyl-8-oxo-7-salicylideneamino-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (33 g) and triphenylphosphine (37.2 g) in N,N-dimethylformamide (90 ml) was added dropwise a solution of iodine (19.5 g) in tetrahydrofuran (30 ml) at 15° C., and the mixture was stirred for 15 minutes. The reaction mixture was poured into isopropyl alcohol (1200 ml) and then stirred for 2 hours. The precipitated crystals were collected by filtration to give (6R,7R)-2-benzhydryloxycarbonyl-8-oxo-7-salicylideneamino-5-thia-1-azabicyclo[4.2.0]oct-2-ene-3-ylmethyl-triphenyl-phosphonium iodide almost quantitatively.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:7][CH2:6]1)=[O:4].ClCC(Cl)=O.[C:23]1(N2CCNCC2)[C:32]2C(=CC=CC=2)C=C[CH:24]=1.C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[C:13](=[CH:24][CH:23]=[CH:32][CH:17]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Agent: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: O=C(CCl)N1CCN(c2cccc3ccccc23)CC1
Yield: 92 %

Procedure:
Compound 49A is prepared according to the procedure described for compound 12A using the following reactants: chloroacetyl chloride (270 ml, 3.45 mmol); 1-(1-naphthyl)piperazine (610 mg, 2.88 mmol); calcium carbonate (860 mg, 8.64 mmol); methyl ethyl ketone (20 ml).
Reaction SMILES: [CH3:1][I:2].[O:3]=[C:4]([C:20]1[N:28]2[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]2)=[CH:22][C:21]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6]>C1COCC1>[I-:2].[CH3:1][S+:17]1[CH2:16][CH2:15][N:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4](=[O:3])[C:20]3[N:28]4[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]4)=[CH:22][C:21]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1
Reactant: O=C(Nc1ccc(N2CCSCC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reactant: CI
Solvent: C1CCOC1
Product: C[S+]1CCN(c2ccc(NC(=O)C(=O)c3c(-c4ccccc4)cc4ccccn34)cc2)CC1
Product: [I-]
Yield: 46.7 %

Procedure:
Methyl iodide (1.6 g, 11.26 mmol) was added to a solution of 2-oxo-2-(2-phenyl-indolizin-3-yl)-N-(4-thiomorpholin-4-yl-phenyl)-acetamide (1 g, 2.2 mmol) in anhydrous THF (25 ml) and then heated to reflux for 8 hr. The reaction mixture was cooled and the resultant precipitate was filtered and washed with cold THF. The solid was dried at 40° C. yielding 1-methyl-4-{4-[2-oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenyl}-thiomorpholin-1-ium iodide (600 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.[C:25](=[O:28])([O-])[O-].[K+].[K+].CN[C@@H]1C[CH2:37][CH2:36][CH2:35][C@H:34]1[NH:39][CH3:40]>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:34]2[C:35]([CH:25]=[O:28])=[CH:36][CH:37]=[CH:40][N:39]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 105 °C
Reaction time: 18 h
Yield: 240.6 %

Procedure:
A mixture of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (168.4 g, 451 mmol), CuI (12.9 g, 67.7 mmol) and potassium carbonate (131 g, 947 mmol) in anhydrous toluene (340 mL) is degassed at room temperature for 30 min. 2-Bromo-pyridine-3-carbaxaldehyde (125 g, 677 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (21.3 mL, 135.4 mmol) are added sequentially. The contents are degassed 30 min. before heating at 105° C. while stirring for 18 hr. LC/MS analysis of the reaction mixture reveals complete consumption of 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (1.5 L), stirred and filtered through a pad of celite. The mother liquid is washed sequentially with 10% ammonium hydroxide (5×100 mL), water (3×100 mL), and brine. It is then dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 50% ethyl acetate in hexane containing 1% triethylamine to afford 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde as a solid (156 g, 72% yield). MS (m/z): 479 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]=[N:38][O:39][CH3:40])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:40][O:39][N:38]=[CH:37][CH2:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@H:6]3[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([O:19][CH3:20])[O:7]3)[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:30][CH:31]=1
Reactant: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of (2S,3S,4R,5S,6S)-2-(4-chloro-3-(4-(2-(methoxyimino)ethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (140 mg, 0.242 mmol) in THF (0.8 mL), methanol (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (20.4 mg, 0.485 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (70 mg, 64.2%).