Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[OH:37].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24][CH3:25])[CH:18]=[C:17]([O:26][CH3:27])[C:16]=2[C@@H:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH3:36])[CH2:30][C@H:29]1[O:37][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN1CC[C@@H](c2c(OC)cc(OC)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@H](OS(C)(=O)=O)C1

Procedure:
Methanesulfonyl chloride (0.178 g, 1.55 mmol), compound of example 129 (0.55 g, 1.2 mmol) and triethylamine (1 mL) in CHCl3 (10 mL), were reacted as described in example 3, method A to obtain (±)-trans-methanesulfonic acid 4-[2-(2-chloro-phenyl)-5,7-dimethoxy-4-oxo-4H-chromen-8-yl]-1-propyl-piperidin-3-yl ester. This was dissolved in dry IPA at 80-90° C., anhydrous NaOAc (0.49 g, 5.98 mmol) was added, and the reaction mixture was processed as in example 3, method A to give an oily residue which was purified using a silica gel column and 1% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:28][C:29]3[CH:36]=[CH:35][C:32]([CH3:33])=[CH:31][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCN)CC1
Reactant: Cc1ccc(C=O)cc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(C)cc2)CC1
Yield: 42.4 %

Procedure:
4-Amino-N-(1-(6-aminohexyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) as starting compound and 4-methylbenzaldehyde (0.66 g) were reacted and treated in the same manner as in Example 121 to give 1.07 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(4-methylbenzylamino)hexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([N:18]1[C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[F:30][C:28]([F:29])([F:31])[C:20]1[CH:19]=[N:18][C:27]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]=2[CH:21]=1.[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17]
Reactant: c1cnc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CC(C(F)(F)F)=CC2=C1CCNC2
Product: CC(C)(C)OC(=O)c1ccc2cccnc2n1
Product: FC(F)(F)c1cnc2c(c1)CNCC2
Temperature: 55 °C

Procedure:
The organic layer from the naphthyridine formation containing N-(tert-butoxycarbonyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (34.2 kg total weight containing 989 g of BOC naphthyridine) was concentrated to an oil. The residue was diluted with methanol (6 L) and the solution was concentrated to an oil. Methanol (6 L) was added to the residue and this solution was concentrated to 2.3 L. The solution was diluted with methanol to a volume of 7.3 L and 4.58 M HCl in IPA (3.6 L) was added. The solution was heated to 55° C. and aged for 1 h. After cooling to room temperature water (5 L) was added. A solution of K2CO3 (2.28 kg) in water (5 L) was then carefully added (pH=10). The mixture was extracted with IPAc (3×10 L). The organic extractions contained 601 g (91%) of deprotected naphthyridine. The combined organic layers were concentrated and the residue was diluted with IPA (6 L) and reconcentrated. The resulting oil was diluted with EPA (6 L) and the solution was concentrated to a total volume of ˜2 L. The solution was filtered through a sintered glass funnel, which was washed with EPA (3×1 L). The combined filtrate and rinses were concentrated to ˜0.5 L and then diluted with IPA (1.95 L). The solution was heated to 60° C. and HCl in IPA (790 mL, 4.33 M by titration) was added over 40 min. During the addition the formation of solids became evident. Heptane (2.75 L) was added over 30 min after which heating was discontinued and the slurry was allowed to cool to room temperature overnight. Additional HCl/IPA (80 mL) and heptane (2×1.38 L) were added. The solids were filtered, washed with 2:1 heptane/IPA (3×550 mL), and dried under vacuum with a nitrogen stream to afford 678.8 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine in 75% yield from BOC naphthyridine (497 g, 73.2 weight percent as free base).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[N:7]=1.CCN([CH:20]([CH3:22])[CH3:21])C(C)C.[C:23]([O-:26])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:3]([C:4]2[O:26][C:23]([C:21]3[CH:20]=[CH:22][CH:10]=[CH:9][CH:8]=3)=[CH:6][CH:5]=2)=[O:2])[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C=Cc1cccc(N)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To acid (36) (100 mg, 0.53 mmol) was added thionyl chloride (0.5 mL), a catalytic amount of DMF (1 drop) and the reaction heated at 50° C. for 30 minutes. After cooling the solvent was concentrated in vacuo and azeotroped with toluene to provide the in situ acid chloride. To the acid chloride was added amine (38) (95 mg, 0.53 mmol) and DIPEA (69 mg, 0.53 mmol) in DCM (2 mL), and the reaction mixture stirred at ambient temperature overnight. K2CO3 (aq) was then added and the aqueous layer extracted with DCM. The organic layer was washed with water, dried (Na2SO4) and the solvent concentrated in vacuo. The residue was partially purified using column chromatography eluting with 50% EtOAc in heptane to give the title compound. Yield: 35 mg, 19%; LC-MS tr 1.67 min; HPLC Purity: 52%; MS (ES+) m/z 349 (M+H)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])=O)(C)(C)C.[Cl:21][C:22]1[CH:23]=[C:24]([NH:38][C:39](OC2C=CC=CC=2)=[O:40])[C:25](=[CH:36][CH:37]=1)[C:26](OCC1C=CC=CC=1)=[O:27]>>[NH2:8][C:9]1[CH:10]=[C:11]([S:17]([N:20]2[C:26](=[O:27])[C:25]3[C:24](=[CH:23][C:22]([Cl:21])=[CH:37][CH:36]=3)[NH:38][C:39]2=[O:40])(=[O:18])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(S(N)(=O)=O)cc1NC(=O)OC(C)(C)C
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1N
Yield: 16 %

Procedure:
400 mg (1.40 mmol) of 3-t-butoxycarbonylamino-4-methoxybenzenesulfonamide and 533 mg (1.40 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 86 mg (yield 16%: 4 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 3.81 (3H, s), 7.26-7.37 (5H, m), 7.77 (1H, s), 7.90 (1H, d), 7.94 (1H, d), 11.73 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.Br[C:12]1[N:17]=[C:16]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)[CH:15]=[N:14][CH:13]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:12]3[N:17]=[C:16]([N:18]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]4)[CH:15]=[N:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cncc(Br)n2)CC1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2cncc(-n3ncc4cnc(Cl)cc43)n2)CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.0 mmol; 307 mg), tert-butyl 4-(6-bromopyrazin-2-yl)-1,4-diazepane-1-carboxylate (2.199 mmol; 785.5 mg), N,N′-Dimethylethylenediamine (4.0 mmol; 352.4 mg; 0.398 mL), cuprous iodide (2.0 mmol; 380.72 mg), and potassium carbonate (2.1990 mmol; 307 mg) in 1,4-Dioxane (15 mL) was purged with Argon, then sealed and stirred at 110° C. overnight. The mixture was cooled to room temperature, then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)pyrazin-2-yl]-1,4-diazepane-1-carboxylate as an off-white solid (217.2 mg, 25%). MS (ESI) m/z: δ 430 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: BrCc1ccccc1
Product: COc1cc(C(=O)/C=C/c2cn(Cc3ccccc3)c3ccccc23)cc(OC)c1OC
Yield: 70.3 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (2.37 g) obtained in Example 1 and benzyl bromide (1.8 g) except that the obtained crude crystals were recrystallized from ethanol and then from a mixed solvent of ethyl acetate and hexane, to give Compound 47 (2.11 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]([OH:17])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]3[O:17][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(-c2ccccc2)noc1C(=O)O
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCc1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
A mixture of 3-phenyl-4-propylisoxazole-5-carboxylic acid, lithium salt (23.12 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1 (30.5 mg, 0.1 mmol), HOBT (16.85 mg, 0.110 mmol), diisopropylethylamine (0.044 mL, 0.250 mmol) and EDC (23.00 mg, 0.120 mmol) was stirred in DMF (1 mL) at rt for 18 hr. Additional EDC (23.00 mg, 0.120 mmol) was added and the reaction mixture was stirred at 60° C. for 5 hr. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (MgSO4) and concentrated to afford an oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-propylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (22 mg, 0.044 mmol, 43.9% yield) as a colorless oil. HPLC retention time=1.84 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=501.21.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@H:26]([C:28](O)=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:31])[C@@H:10]([NH:25][C@@H:26]([CH3:27])[C:28]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)NS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-((S)-1-carboxy-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (600 mg, 1.37 mmol) in DCM (7 mL) and saturated aqueous NaHCO3 solution (2 mL) was added triphosgene (407 mg, 1.37 mmol). After being stirred for 0.5 hours, the reaction mixture was diluted with EtOAc and stirred for additional 0.5 hours until generation of gas was completed. The organic layer was separated, washed with brine and concentrated. This was dissolved in DCM (7 mL) and methanesulfonamide (195 mg, 2.06 mmol) was added. After being stirred at rt for 1 hour, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-((S)-2-methanesulfonylamino-1-methyl-2-oxo-ethylamino)-propionic acid benzyl ester. MS: m/z (MW) 515; HPLC retention time 1.58 min (HPLC condition A).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])[C:19]([Cl:31])=[CH:18][N:17]=1.Cl.[Na]>O.CC(O)C>[Cl:31][C:19]1[C:20]([NH:22][CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:30])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NC4CCCCNC4=O)n3)cc2CC1
Temperature: 120 °C
Yield: 26 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (75 mg 0.20 mmol), 3-(2,5-Dichloro-pyrimidin-4-ylamino)-azepan-2-one (57 mg, 0.30 mmol) and 81 μl of 4N HCl in dioxanes were combined into 1 ml IPA in a microwave tube. The reaction was heated to 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-20% methanol in methylene chloride as the eluent to yield 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-azepan-2-one (22.33 mg, 19%). MP: 232-234° C.; 1H-NMR (CDCl3) δ 7.99 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.16 (s, 1H), 7.08 (d, J=8 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J=6 Hz, 1H), 6.30 (br s, 1H), 4.69 (q, J=9.9, 5.56 Hz, 1H), 3.32 (m, 2H), 2.92 (m, 4H), 2.72-2.52 (m, 6H), 2.25 (d, J=3.9 Hz, 1H), 2.05 (d, J=4.2 Hz, 1H), 1.95-1.65 (m, 2H), 1.60-1.40 (m, 2H), 1.08 (t, J=7 Hz, 3H); LC/MS (ESI+): 429 (M+H).
Reaction SMILES: N12CCCCC1C=NCCC2.[N+:12]([CH3:15])([O-:14])=[O:13].[C:16]([O:21][CH3:22])(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>CO>[CH3:19][CH:18]([CH2:15][N+:12]([O-:14])=[O:13])[CH2:17][C:16]([O:21][CH3:22])=[O:20]
Reactant: C/C=C/C(=O)OC
Reactant: C[N+](=O)[O-]
Agent: C1=NCCCN2CCCCC12
Solvent: CO
Product: COC(=O)CC(C)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 144 h
Yield: 66.2 %

Procedure:
1,5-Diazabicyclo[5,4,0]undec-5-ene (6 ml) is added to a solution of nitromethane (91.5 g) in methanol (500 ml). The resulting mixture is heated to 60° C. and methyl crotonate (100 g, 1 m) is added under nitrogen. The mixture is then stirred for 6 days at 60° C. after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2N hydrochloric acid (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3-methyl-4-nitrobutanoate (106.6 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N-dimethyl-1,2-ethanediamine by following the procedures in Example 79c. LC-MS m/z 562 (M+H)+; 1H-NMR (MeOD) 2.15 (m, 6 H), 2.36 (m, 4 H), 2.65 (m, 1 H), 3.27 (m, 2 H), 6.38 (d, J=8.4 Hz, 1 H), 7.17 (m, 1 H), 7.25 (m, 2 H), 7.49 (m, 2 H), 7.59 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, J=8.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.ClCCl>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH2:11][Br:12])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(Br)cc1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1CBr
Temperature: 90 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask, methyl 5-bromo-3-methylthiophene-2-carboxylate (1.50 g, 6.38 mmol) was dissolved in tetrachloromethane (30 mL). To above solution was added 1-bromopyrrolidine-2,5-dione (1.14 g, 6.38 mmol, 1.0 eq) and diphenylperoxyanhydride (0.155 g, 0.638 mmol, 0.1 eq). The reaction was stirred at 90° C. for 18 hr. To above reaction was added dichloromethane (30 mL), washed with aqueous sodium bicarbonate, brine and water. The organic phase was dried over MgSO4, filtered and concentrated. The crude was used in next step without purification. LC-MS (IE, m/z): 337.4 [M+N]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>CO>[CH2:3]([C:10]1[C:11]([O:16][CH3:17])=[N:12][CH:13]=[C:14]([Br:1])[CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ncccc1Cc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cc1Cc1ccccc1

Procedure:
0.12 ml of bromine was added to a mixture of 430 mg of 3-benzyl-2-methoxypyridine, 460 mg of sodium bicarbonate and 10 ml of methanol under stirring in an ice bath, followed by stirring at room temperature for 8 hours. The mixture was partitioned by adding an aqueous sodium thiosulfate solution and ethyl acetate thereto. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with 5% ethyl acetate/hexane, to give 140 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][C:13](=[O:35])[CH:14]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH3:11][O:12][C:13](=[O:35])[CH:14]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(=O)C(COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CSc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-fluorothiophenol (1.24 g, 9.65 mmol) in N,N-dimethyl formamide (10 ml) was treated with sodium hydride (240 mg, 9.37 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. 2-tert-Butoxycarbonylamino-3-(toluene-4-sulfonyloxy)-propionic acid methyl ester (3 g, 8.04 mmol) in N,N dimethyl formamide (ml) was added, the resulting mixture was stirred for two hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with water (2*80 ml) and brine. The organic layer was dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel, 2-tert-butoxycarbonylamino-3-(4-fluoro-phenylsulfanyl)-propionic acid methyl ester (2.28 g, 83%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[NH2:12].[CH3:13][O:14][CH2:15][C:16](OC)=[O:17]>COC(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[NH:12][C:16](=[O:17])[CH2:15][O:14][CH3:13]
Reactant: COCC(=O)OC
Reactant: NC1CCOc2c(F)cccc21
Solvent: COC(C)(C)C
Product: COCC(=O)N[C@@H]1CCOc2c(F)cccc21
Yield: 16 %

Procedure:
A mixture of 8-fluorochroman-4-amine (3.40 g), methyl 2-methoxyacetate (2.44 g) and Novozyme 435 (Aldrich, 0.68 g) in anhydrous tert-butyl methyl ether (75 mL) was heated at reflux under argon for two hours (at which time the ratio of acylated to unacylated product was 1:1 by HPLC). The solid that formed upon cooling was collected via filtration and dissolved in EtOAc. The mixture was filtered to remove the biocatalyst and washed once with 0.5M HCl to remove any lingering (S)-amine. The solvent was evaporated and the product was recrystallized from tert-butyl methyl ether to yield (R)—N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g). The reaction solvent and recrystallization mother liquor was washed three times with 0.5 M HCl and concentrated to yield additional (R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.83 g). The combined acidic aqueous layers were made basic by NaOH and extracted with methylene chloride to yield (S)-8-fluorochroman-4-amine (5a) (1.6 g). A solution of (R)-N-(8-fluorochroman-4-yl)-2-methoxyacetamide (0.78 g) in 8M HCl in EtOH (50 mL) was heated at reflux for four hours. The solvents were removed from the cooled reaction mixture, the resulting solid was taken up in 50 mL of 0.5M NaOH, salted out with NaCl(s), and extracted four times with methylene chloride to yield (R)-8-fluorochroman-4-amine (0.48 g (87%)) (5b). The % ee was checked via chiral HPLC: Chiralcel OD-H (0.46×25 cm analytical column, Daicel Chemical Industries) method: isocratic 5% (0.05% TFA/EtOH) 95% (0.05% TFA/Hex), Rt=7.2 min (S)-enantiomer, Rt=9.2 min (R)-enantiomer.