Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]2[CH:13]=[C:9]([CH:7]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]([CH3:22])=[N:11]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1cc(F)ccc1-n1cc(C(O)C2CCCCC2)c(C)n1
Product: Cc1cc(F)ccc1-n1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 60.8 %

Procedure:
Using cyclohexyl[1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 21(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.39 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.48 g, 60%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][OH:13].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>C(OCC)(=O)C>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:15]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13]1
Reactant: COC(=O)c1ccc(N)c(CO)c1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)COC(C(Cl)(Cl)Cl)N2
Reaction time: 0.08 h

Procedure:
Methyl 4-amino-3-hydroxymethylbenzoate (1 g.) and anhydrous chloral (1 ml.) were mixed together, initially with external ice-cooling, and then on a steam bath for 5 minutes. The product was dissolved in ethyl acetate (100 ml.) and the solution was washed with water (50 ml.), then dried. The solvent was evaporated, and the residue was crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80 C.) to give methyl 1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine-6-carboxylate, m.p. 178°-179° C.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].ICC[OH:14]>>[C:1]([OH:9])(=[O:14])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: OCCI
Product: CCCC(CCC)C(=O)O
Temperature: 100 °C
Yield: 138.7 %

Procedure:
To the product of Example 87 (4.87 g, 30 mmol), 2-iodoethanol (5.16 g, 30 mmol) was added with stirring and cooling in an ice bath. The neat mixture was then heated to 100° C. in a water bath for 10 minutes, then removed from the heat and stirred for an additional 10 minutes. The reaction mixture was then dissolved in 50 ml of ether, washed with water (1×30 ml), 5% NaOH (2×30 ml), and again with water (2×30 ml). The ether layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. A light yellow liquid product was obtained in 67% yield from valproic acid (6.0 g). Silver nitrate gave a bright yellow precipitate. NMR analysis confirmed the identity of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:59]1([CH2:66][CH2:67][OH:68])[CH2:65][CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:62]4[CH2:63][CH2:64][CH2:65][N:59]([CH2:66][CH2:67][OH:68])[CH2:60][CH2:61]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OCCN1CCCNCC1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCCN(CCO)CC1
Reaction time: 0.5 h

Procedure:
A solution of 0.20 g (0.50 mmol) of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 0.21 g (0.50 mmol) of HATU were dissolved in 8 ml of DMF at RT. While stirring, 0.16 g=0.22 ml (1.60 mmol) of Et3N were added drop by drop. After 30 min, a solution of 0.076 g (0.50 mmol) of 2-[1,4]diazepan-1-yl-ethanol in 2 ml of DMF were added drop by drop and stirring was continued for 20 hours at RT. The reaction mixture was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0-9:1) to afford the title compound as colorless oil. MS: 507.4 (MH+, 1 Cl).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:19][C:20]([S@@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CO.C([O-])(O)=O.[Na+]>ClCCl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12](/[CH:15]=[N:25]/[S@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[S@](=O)/N=C/c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde (35.25 g, 138.9 mmol) was suspended in anhydrous dichloromethane (470 mL) in a 3-necked 1 L flask with overhead stirrer, condenser and internal temperature. (S)-(−)-2-methyl-2-propanesulfinamide (17.13 g, 141.3 mmol) was added followed by titanium(IV) ethoxide (37.3 mL, 178 mmol). This gave a yellow solution which was heated to reflux for 3 h. The heating was discontinued and the reaction placed in an ice bath. When the internal temperature was −10° C., anhydrous methanol (246 mL) was added followed by sat. aq. NaHCO3 (71 mL). Solid crashed out which was stirred for 2 h. The solids were filtered off with a Buchner funnel using ethyl acetate to aid in transfer. Several portions of ethyl acetate were used to rinse the solid. The solid was added back into the 3-necked flask and mechanically stirred for 20 min with ethyl acetate. This was refiltered. This process was repeated to remove most of the product. The filtrate was dried over Na2SO4 and concentrated in vacuo to give (S)-2-methyl-propane-2-sulfinic acid 1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-meth-(E)-ylideneamide (49.00 g, 99%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 9.25 (s, 2H) 8.70 (s, 1H) 8.66 (d, J=8.2 Hz, 2H) 7.79 (d, J=8.2 Hz, 2H) 1.31 (s, 9H); MS (M+1): 356.1.
Reaction SMILES: N[C:2]1[C:3](O)=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(CCCCOC2C=CC(C(Cl)=O)=CC=2)C=CC=CC=1.Cl>CC(C)=O>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1O
Agent: Cl
Agent: O=C(Cl)c1ccc(OCCCCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3'-Amino-2'-hydroxyacetophenone (1.51 g, 10 mmol) was dissolved in 50 ml of acetone, and potassium carbonate (6.90 g, 50 mmol) was added to the solution. 4-(4-Phenylbutoxy)benzoyl chloride (2.89 g, 10 mmol) was added dropwise to the mixture under stirring at 0° C., and stirring was conducted further for 3 hours. The resultant reaction mixture was poured into a 10% hydrochloric acid (100 ml) to conduct extraction with chloroform. An organic layer was washed with water, dried and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. Crystals obtained from a fraction eluted with chloroform were recrystallized from ethanol to obtain 2.82 g (yield: 70%) of 2-hydroxy-3-[4-(4-phenylbutoxy)benzamido)]acetophenone.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH:11]2[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5])C.CO.O>[OH-].[K+]>[CH:8]12[CH2:9][CH2:10][CH:11]1[CH2:12][C:6]([C:13]([OH:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(C(=O)OCC)CC2CCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(C(=O)O)CC2CCC2C1
Yield: 87.4 %

Procedure:
A solution of 10.3 g of 3,3-bis(ethoxycarbonyl)bicyclo[3.2.0]heptane in 68 ml of 16% potassium hydroxide in 1:1 methanol-water was refluxed for 16 hr under argon. The solvents were removed in vacuo and the residue dissolved in a minimum amount of water. The solution was acidified with concentrated hydrochloric acid and the precipitated acid isolated by vacuum filtration to yield 6.9 g of bicyclo[3.2.0]heptane-3,3-dicarboxylic acid as a white solid, mp 161°-170°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[C:12](=O)[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[CH3:29][NH2:30]>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][C@@H:11]([CH2:15][CH3:16])[C@H:12]([NH:30][CH3:29])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: CN
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)=O
Product: CC[C@H](Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)[C@@H](C)NC

Procedure:
The title compound was prepared by a reductive amination as shown above starting with 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinic acid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl3)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)[C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][N:8]=1)=[O:5])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[CH2:44][N:45]1[C:54]2[C:49](=[CH:50][C:51](I)=[CH:52][CH:53]=2)[C:48](=[O:56])[C:47]([C:57]([O:59]CC)=[O:58])=[CH:46]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Cs+].[Cs+].Cl>O1CCOCC1.O.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.CO>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[CH2:44][N:45]1[C:54]2[C:49](=[CH:50][C:51]([C:10]3[CH:9]=[N:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:11]=3[C:13]3[S:14][CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[N:17]=3)=[CH:52][CH:53]=2)[C:48](=[O:56])[C:47]([C:57]([OH:59])=[O:58])=[CH:46]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(CC2CCCCN2C(=O)OC(C)(C)C)c2ccc(I)cc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CC2CCCCN2C(=O)OC(C)(C)C)cn1
Temperature: 100 °C

Procedure:
6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 17, 0.448 g, 1.24 mmol) and ethyl 1-((1-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 72, 0.672 g, 1.24 mmol) were combined and diluted with dioxane (6 mL). A solution of Cs2CO3 (0.689 g, 2.11 mmol) in water (1.5 mL) was added. Tetrakis(triphenylphosphine)palladium(0) (0.144 g, 0.12 mmol) was added. The mixture was heated at 100° C. overnight. After cooling to RT, water and MeOH were added and the mixture was conconcentrated in vacuo. The residue was acidified with 1 N aq HCl and then dried on a lyophilizer. The resultant solid with diluted with EtOAc and water and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and conconcentrated in vacuo to give the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.O>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)Cc1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-butyl{2-[(diphenylmethylidene)amino]-pyridin-4-yl}acetate (35 mg, 0.94 mmol) was dissolved in 1:1 mixture of THF/water (5 mL) and treated with 500 μL of a 1N aqueous hydrochloric acid solution. The reaction was allowed to stir at ambient temperature for 30 minutes and then concentrated in vacuo. The crude residue was dissolved in DCM and washed with a saturated aqueous sodium bicarbonate solution. The organic layers were dried over sodium sulfate, filtered and concentrated to afford crude title compound which was used without further purification: LC-MS: (M+H)+209.
Reaction SMILES: [F:1][CH:2]([F:11])[P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6].C([N-]C(C)C)(C)C.[Li+].Br[C:21]1([CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]1[CH3:27]>O1CCCC1>[CH3:28][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:2]([P:3](=[O:7])([O:8][CH2:9][CH3:10])[O:4][CH2:5][CH3:6])([F:1])[F:11]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: CC1C=CC=CC1(C)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)Cc1ccccc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
30 mmol (5.64 g) of diethyl difluoromethane phosphonate dissolved in 30 ml of anhydrous tetrahydrofuran (THF) are slowly added to a stirred solution of (LDA) lithium diisopropylamide (prepared at 0° C. from 31 mmol of n-butyllithium and 30 mmol of diisopropylamine in 30 ml of anhydrous THF) at -78° C. under argon. After 30 minutes, 45 mmol (8.33 g) of 2-bromo-o-xylene are added to the reaction mixture which is stirred at -78° C. for 15 hours and quenched by adding 20 ml of an aqueous saturated solution of ammonium chloride. The crude mixture is evaporated to dryness; the residue is suspended in 50 ml of water and extracted 3 times with 100 ml of ethylacetate. The organic layers are dried over sodium sulfate, filtered and evaporated to give approximately 8 g of crude product which is purified by flash chromotography on silica gel affording 3.6 g of 1A (41% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH:18]([C@@H:20]1[N:24]([CH3:25])[C:23](=[O:26])[CH2:22][C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C@@H:18]([OH:19])[C@@H:20]3[N:24]([CH3:25])[C:23](=[O:26])[CH2:22][C@@H:21]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Fc1ccc(-c2cccs2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc(F)cc2)s1
Temperature: -20 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a −65° C. solution of 2-(4-fluorophenyl)thiophene (Intermediate O; 853.6 mg, 5.79 mmol) in THF (5 mL) was added a solution of n-BuLi (2.5M in hexane, 1.8 mL, 4.5 mmol). The reaction mixture was allowed to warm to −20° C. over the period of 1 h. After cooling down to −65° C. again, a solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 6.38 mmol) in THF (5 mL) was added. The reaction mixture was stirred for 1 h, while allowing to warm to −20° C., then treated with a saturated NH4Cl solution (15 mL). The resulting mixture was extracted with EtOAc (4×15 mL), dried (MgSO4) and concentrated under reduced pressure. The crude brown solid was triturated (Et2O/hex) to give (±)-(4R*,5R*)-5-{(1S*) [5-(4-fluorophenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (330 mg, 24%) as a fine brown solid: mp 110° C. (dec); TLC (EtOAc) Rf 0.52.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:24])[F:25])[C:9]=2[Cl:27])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 5-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (350 mg, 0.783 mmol) in N,N-dimethylformamide (12 ml) was added N-chlorosuccinimide (1.05 g, 7.83 mmol) at room temperature. After the mixture was stirred for 18 hr, 1.05 g of N-chlorosuccinimide was added. The resulting mixture was stirred for further 36 hr. 20 nm of saturated aqueous sodium thiosulfate and 50 nm of diethyl ether were added and the two-phase-mixture was stirred for 0.5 hr. The separated organic layer was washed with water (20 ml×3) and dried over magnesium sulfate. Removal of solvent gave a pale yellow gum, which was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (1:3) to afford 236 mg (63%) of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].CCN=C=N[CH2:14][CH2:15][CH2:16][N:17](C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1(N)CC1>>[CH:16]1([NH:17][C:1](=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15]1
Reactant: CCC/C=C/C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCC/C=C/C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipitate formed. The slimy was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide compound 37 as a fine white solid. 1H NMR (500 MHz, d6-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H), 5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H), 1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:21][C:19]1[N:20]=[C:15]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncc(Br)cc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Temperature: 120 °C

Procedure:
A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237 mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1.0 mmol), DIPEA (0.6 mL) and 5 mL of ethanol. The tube was heated at 120° C. under microwave irradiation for 15 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound. LCMS (method E): [MH]+=406/408/410, tR=5.803 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH:29]=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:52][CH2:53][CH:54]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C=O)C>ClCCCl>[CH:39]([O:38][C:36]([C:33]1([O:32]/[N:31]=[C:14](/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)\[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][NH:52][CH2:53][CH:54]3[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:55]3)[CH:26]=[N:25]2)=[O:16])[CH2:35][CH2:34]1)=[O:37])([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(C=O)n2)cs1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CNCC3CN(C(=O)OC(C)(C)C)C3)n2)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-formyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (150 mg, 0.21 mmol) in DCE (4 ml) at 0° C. was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (78 mg, 0.420 mmol), sodium triacetoxyborohydride (66.7 mg, 0.315 mmol), and DMF (0.4 mL). After stirring at rt for 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq) and diluted with 10% EtOH/DCM (40 mL). The organic layer was separated, dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was used as such in the following step. LCMS: Rt=0.55 min, m/z=885.5 (M+1). Method 2m_acidic.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:27])[C:4]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OC(C)(C)C)[CH2:6][CH2:5]1.CO.C(Cl)(Cl)[Cl:31]>C(Cl)(Cl)Cl>[ClH:31].[ClH:1].[ClH:31].[CH3:27][N:3]([CH3:2])[C:4]1([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][CH3:14])[CH2:6][CH2:5]1
Reactant: CN(CCCN1CCC(c2cccs2)(N(C)C)CC1)C(=O)OC(C)(C)C
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: CO
Product: CNCCCN1CCC(c2cccs2)(N(C)C)CC1
Yield: 98 %

Procedure:
HCl gas was passed through a solution of 1.5 g (1 eq) tert-butyl 3-(4-(dimethylamino)-4-(thiophen-2-yl)piperidin-1-yl)propyl(methyl)carbamate in 30 ml chloroform at 0° C. for ˜30 min. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the solvent was removed under reduced pressure. After trituration with diethyl ether, 1.5 g (98%) of product were obtained in the form of a white solid.