Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:7][NH:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CCOC(C)=O>[F:1][CH:2]1[CH2:7][N:6]([C:23]([C:21]2[N:22]=[C:18]([CH3:17])[S:19][C:20]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)CN1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)OC(C)(C)C)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (5-fluoropiperidin-2-yl)methylcarbamate (0.43 mmol, 0.1 g), 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (made as described in the literature: see for instance, WO2008/020405, 0.47 mmol, 0.1 g), diisopropyl ethyl amine (0.47 mmol, 0.08 mL) and HATU (0.47 mmol, 0.18 g) in dimethyl acetamide (2 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 1N NaOH and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo to provide desired tert-butyl (5-fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methylcarbamate which was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N)[CH2:17][NH2:18]>CN(C)C=O.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:17]#[N:18])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1c([N+](=O)[O-])ccc2c(Br)cccc12
Reactant: NCCN
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c(N)c([N+](=O)[O-])ccc12
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 1,6 g (5,9 mmol) 1-amino-5-bromo-2-nitronaphthalene in 50 ml dimethylformamide was added 1,1 g (11,8 mmol) cuprous cyanide. The reaction mixture was refluxed for 5 h, and then poured into a solution of 2,5 ml ethylenediamine in 80 ml water. Stirring was continued for 15 min., and then the precipitate was filtered off and washed with water and boiling ethyl acetate to give 1,0 g (80%) 1-amino-5-cyano-2-nitronaphthalene, m.p. 260-262° C. IR (KBr): 2200 cm-1 (nitrile function).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O-:15])=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([Cl:26])=[O:15])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1nnnn1Cc1ccccc1
Temperature: 15 °C

Procedure:
The potassium salt produced in Example 2, and pyridine are stirred at 6° C. in benzene followed by rapid addition of oxalyl chloride. After stirring one half hour at 15° C. the mixture is stripped at 15° C., and scrubbed with two portions of benzene at 15° C. to yield 1-benzyl-1H-tetrazole-5-carbonyl chloride.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][C:21]#[N:22])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.00 g, 16.9 mmol, 1.00 equiv), chloroacetonitrile (1.40 mL, 21.9 mmol, 1.30 equiv, Aldrich), potassium carbonate (4.67 g, 33.8 mmol, 2.00 equiv), and potassium iodide (561 mg, 3.38 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under-argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.01 g (86%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.P(Br)(Br)[Br:28].O>CCOCC>[Br:28][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCC#CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCC#CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 18.8 g of 2-nonadecyn-1-ol, 110 ml of ether, 1.14 ml of pyridine and 5.7 ml of phosphorous tribromide in 25 ml of ether is heated at reflux for 2 hours, then stirred at room temperature for 2 hours, poured into water and washed with hydrochloric acid. The solution is evaporated and filtered through silicon dioxide with hexane, to give 16.9 g of the desired product as a white solid, mp. 34°-35° C.
Reaction SMILES: Br[Si](C)(C)C.C[O:7][P:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:33]([NH:34][C:35](=[O:45])/[C:36](/[C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)=[N:37]\[O:38][CH3:39])[C:32](=[O:46])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([O:28][C:29](=[O:31])[CH3:30])[CH3:27])=[O:24])=[O:14])([O:10]C)=[O:9].[CH3:47][Si](NC(OCC)=O)(C)C>ClCCl>[CH:42]([O:41][CH:40]([CH3:36])[CH3:44])([CH3:43])[CH3:47].[P:8]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:33]([NH:34][C:35](=[O:45])/[C:36](/[C:40]3[O:41][CH:42]=[CH:43][CH:44]=3)=[N:37]\[O:38][CH3:39])[C:32](=[O:46])[N:21]2[C:22]=1[C:23]([O:25][CH:26]([O:28][C:29](=[O:31])[CH3:30])[CH3:27])=[O:24])=[O:14])([OH:9])([OH:10])=[O:7]
Reactant: CCOC(=O)N[Si](C)(C)C
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(=O)NP(=O)(OC)OC)CS[C@H]12)c1ccco1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(=O)NP(=O)(O)O)CS[C@H]12)c1ccco1
Yield: 133.8 %

Procedure:
Bromotrimethylsilane (0.31 g) in dichloromethane (3 ml) was added to a cooled (0°) stirred mixture of (R and S)-1-acetoxyethyl (6R,7R)-3-dimethoxyphosphorylcarbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (0.62 g) and trimethylsilylurethane (0.16 g) in dry dichloromethane (12 ml) in a nitrogen atmosphere. After 2.5 hours the reaction mixture was evaporated in vacuo to a foam. This foam was dissolved in ethyl acetate (30 ml) although a slight precipitate remained. The filtered organic solution was treated with saturated aqueous sodium bicarbonate solution (30 ml) and the aqueous solution was layered with butan-1-ol (20 ml) and acidified to pH 0.5 by addition of concentrated hydrochloric acid. The aqueous phase was extracted with butan-1-ol (2×15 ml) and the combined organic extracts were evaporated in vacuo to give a solid. Trituration of this solid with di-isopropyl ether afforded the title ester (0.396 g) as a solid; νmax (Nujol) 3270 (NH), 1788 (β-lactam), 1734 (CO2R) and 1684 and 1540 cm-1 (CONH); τ (DMSO-d6) 0.18 (d, J 8 Hz, NH), 2.9 to 3.4 (broad m, 2 superimposed q, CHCH3), 4.14 (m, 7-H, mixture of diastereoisomers), 4.76 (m, 6-H, mixture of diastereoisomers), 7.92 (s, OCOCH3) and 8.52 (d, J 5 Hz, CHCH3).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C[N:7]([CH:9]=O)[CH3:8].[CH2:11]([C:13]1[CH:17]=[C:16]([OH:18])N(C)[N:14]=1)[CH3:12].C([O-])([O-])=O.[K+].[K+]>ClCCl>[Cl:3][C:9]1[N:7]([CH3:8])[N:14]=[C:13]([CH2:11][CH3:12])[C:17]=1[CH:16]=[O:18]
Reactant: CCc1cc(O)n(C)n1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCc1nn(C)c(Cl)c1C=O
Temperature: 0 °C
Yield: 61.7 %

Procedure:
POCl3 (236.88 g, 1.543 mol, 144 mL) was added dropwise at 0° C. to DMF (59 g, 0.808 mol). The reaction mixture was then diluted with dichloromethane (200 mL), and: 3-ethyl-1-methyl-1H-pyrazol-5-ol (84.5 g, from Step 1) was added while stirring at 0° C. The mixture was refluxed for 3 h and then stirred overnight at room temperature. After this, ice-cold water (500 mL) was added rapidly at 0° C. to the reaction mixture in order to decompose the formylation agent. The organic layer was separated, and the aqueous phase extracted with chloroform several times. The organic layers were then washed with K2CO3 solution to obtain a weak alkaline media, dried over Na2SO4 and evaporated to give 51.2 g of an oily substance. The residual reaction mass was neutralized with K2CO3 to obtain a weak acidic media and extracted with chloroform. The combined extracts were concentrated and the residue purified by chromatography (dichloromethane) on a silica gel to give 71.3 g (62%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][CH:50]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:47])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][CH:50]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:47])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCCO)c(NS(C)(=O)=O)c3)cc12
Yield: 11.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-hydroxypropoxyl)phenyl) methanesulfonamide (60 mg, 0.08 mmol) was hydrolyzed by lithium hydroxide (6 mg, 0.25 mmol), THF/methanol/water (1/1/0.5 ml) to afford 5 mg (1.1% yield) of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 11.85 (s, 1H), 8.90 (s, 1H), 8.47 (s, 1H), 7.77 (s, 1H), 7.52-7.41 (m, 4H), 7.15-7.00 (m, 4H), 5.32 (s, 2H), 4.60 (b, 1H), 4.13 (t, 2H), 3.63-3.61 (t, 2H), 2.97 (s, 3H), 2.17-2.13 (d, 6H), 1.93 (m, 2H). MS: m/z=564.1 (M+1), HPLC: 98.85% (method-B).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>CN1C(=O)CCC1.CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:13][CH:14]=1
Reactant: N#Cc1cccnc1Cl
Reactant: NCc1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1NCc1ccncc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 15.5 %

Procedure:
To a stirred solution of 2-chloro-nicotinonitrile (Aldrich, 10.4 g, 75.06 mmol) in dry NMP (40 ml) was added 4-(aminomethyl)pyridin (15.2 ml, 150.26 mmol). The reaction mixture was heated to 130° C., and stirred at this temperature for 20 hours. The mixture was cooled to room temperature and diluted with EtOAc (500 ml) and washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The remaining red-brown solid material was recrystallised from ethanol affording the title compound (7.73 g) as an off-white solid. The filtrate was evaporated under reduced pressure, redissolved in 2% methanol/EtOAc (v/v) and filtrated through a pad of silica gel. The filtrate was evaporated under reduced pressure and the residue was recrystallised from ethanol and gave an additional amount of the title compound (2.44 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][N:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:19]2[CH:18]=[N:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g) and 2-nitro-5-chloropyridine (21.9 g) in N,N-dimethylformamide (120 mL) was added cesium carbonate (45 g). The mixture was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate (800 mL) and washed three times with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (2% ethyl acetate in dichloromethane) to give the title compound.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16](NC)=[O:17])(=[O:14])=[O:13])=[CH:3][Cl:4]>ClC1C=CC=CC=1>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:13])=[O:14])=[CH:3][Cl:4]
Reactant: CNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Yield: 98.1 %

Procedure:
9.8 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-methyl urea are solved in 200 ml of chlorobenzene. The solution is dried by azeotropic desitlling off of 20 ml of the solvent. 5.3 g of phosgene are introduced into this solution within 45 minutes at a temperature of 120°-130° C. Evaporation of the reaction mixture to dryness yields 8.7 g of 2-(1,2-dichlorovinyloxy)-phenylsulfonylisocyanate in form of a yellowish oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14](=[O:23])[C:13]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14](=[O:23])[NH:15]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Product: O=c1[nH]c2cc(Cl)ccc2c(NS(=O)(=O)c2ccccc2)c1-c1ccccc1

Procedure:
Benzene sulphonylchloride (0.94 ml) and 4-amino-7-chloro-3-phenyl-2(1H)-quinolone (1 g) (Example 2) were reacted in a similar manner to that as described in Example 4. An additional step was required to remove the tert butyldimethylsilyl protecting group using methanolic-HCl for 20 mins to afford the title compound (0.050 g); mp 268° C. (ethanol); δ (360 MHz, DMSO-d6) 7.14 (6H, m, aromatics), 7.32 (5H, m, aromatics), 7.49 (1H, m, aromatics), 7.67 (1H, d, J =8.7 Hz, 5H), 10.02 (1H, br s, 4NH), 12.15 (1H, br s, 1NH); m/z 410 (M+).
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[OH:20][CH2:21][CH2:22][C:23](=O)[CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH:23]([CH3:24])[CH2:22][CH2:21][OH:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: FC(F)(F)c1nc2cc3c(c(Br)c2o1)CCNCC3
Reactant: CC(=O)CCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(CCO)N1CCc2cc3nc(C(F)(F)F)oc3c(Br)c2CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
A mixture of 10-bromo-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (250 mg, 1 eq), 4-hydroxy-butan-2-one (0.077 ml, 1.2 eq), acetic acid (0.042 ml, 1 eq) and sodium triacetoxyborohydride (314 mg, 2 eq) in THF (2.5 ml) was stirred at room temperature for 20 hours. Additional 4-hydroxy-butan-2-one (0.24 eq) and sodium triacetoxyborohydride (0.4 eq) were added and the mixture was stirred for 5 hours. Then, the mixture was diluted with DCM and washed with 5% NaHCO3 and brine. The organic phase was dried (Na2SO4) and concentrated. The crude was purified on silica gel (DCM/MeOH/conc.NH4OH, 100/2.5/0.25) providing the title compound (218 mg, 72% yield).
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].CCN=C=NCCCN(C)C.[CH2:52](O)[CH2:53][OH:54]>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([O:40][CH2:52][CH2:53][OH:54])=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Reactant: OCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)OCCO)cc3)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.150 g, 0.270 mmol) was dissolved in DMF (2.7 mL) then treated with EDCI (0.062 g, 0.324 mmol) and DMAP (0.003 g, 0.027 mmol) and allowed to stir at 60° C. for 30 min. Ethylene glycol (3 mL) was then added and the reaction was allowed to stir for 4 hours. The reaction mixture was then cooled to room temperature and dissolved in EtOAc (10 mL) and extracted with brine (3×10 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then redissolved in EtOAc (1 mL) and triturated with Hexanes (20 mL) causing the product to precipitate out. The resulting white solid to give the title compound (0.125 g, 77%).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[ClH:1].[CH2:19]([N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:3]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CCC1CCN(Cc2ccccc2)CC1

Procedure:
A suspension of (piperidin-4-yl)ethylcarboxylate hydrochloride (8.6 g, 44.4 mmol) and K2CO3 (24.5 g, 0.17 mol) in acetone (200 ml) was added benzylbromide (9.11 g, 53.3 mmol) and heated to reflux for 12 h. The solvent was evaporated in vacuo and the residue added H2O (200 ml). The aqueous layer was extracted with Et2O (3×100 ml) and the organic extracts dried over Na2SO4, filtered and evaporated in vacuo. The residue was dissolved in acetone and HCl bubbled into the solution to give the hydrochloride precipitate. The precipitate was filtered, dried and recrystallized from acetone to give the expected product as a white solid (11.03 g, 87.6%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[N:22]=[CH:21][CH:20]=[C:19]([F:23])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:20]1[CH:21]=[N:22][C:10]([F:9])=[C:11]([C:19]=1[F:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)c1c(F)ccnc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(F)ncc(Cl)c1F
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
Into a solution of LDA in THF (20 mL, 12 mmol) was added a solution of tert-butyl 2,4-difluoronicotinate (2.14 g, 10 mmol) in THF (12 mL) at −78° C. The mixture was stirred for 30 min and then a solution of hexachloroethane (2.96 g, 12.5 mmol) in THF (7.0 mL) was added. The temperature was allowed to rise to 0° C. The reaction was then quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate and the organic layers were combined, dried over sodium sulfate, evaporated and purified by silica chromatography (0-8% ethyl acetate in hexanes) to give tert-butyl 5-chloro-2,4-difluoronicotinate (1.2 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14]C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:16][NH2:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([NH:16][NH2:17])=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Reactant: NN
Product: COc1ccc(C2(C(=O)NN)CC2)cc1
Temperature: 120 °C
Yield: 82.6 %

Procedure:
A mixture of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (0.90 g, 4.4 mmol) and hydrazine (0.65 mL, 21 mmol) was heated at 120° C. for 2 h. After cooling, the excess hydrazine was removed under reduced pressure. The residue was treated with water, filtered and washed with water to give the desired product (750 mg, 83%). Analytical LCMS: (M+H)+=207.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=1)[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])#[N:2].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].[Br-].[Al+3].[Br-].[Br-].[ClH:25]>ClCCl>[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]1[N:18]=[C:17]([C:16]([Cl:19])([Cl:15])[Cl:25])[N:18]=[C:1]([C:3]2[CH:4]=[C:5]([CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:2]=1
Reactant: COC(=O)C=Cc1cccc(C#N)c1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)C=Cc1cccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)c1
Temperature: 25 °C

Procedure:
Methyl 3-cyanocinnamate (42 pw) is added to a mixture of trichloroacetonitrile (194.4 pw) and aluminum bromide (7.2 pw) in the absence of moisture and at about 25° C. Hydrogen chloride is then introduced over a period of 3 hours with stirring, while keeping the temperature constant. Stirring is discontinued, and the mixture is allowed to react further overnight. In this step, too, a constant temperature of 25° C. is maintained. The solidified mixture is dissolved in 800 pw of dichloromethane, washed with water, and the organic phase is dried over sodium sulfate. Evaporation of the solvent gives a white residue, which is recrystallized from methanol or benzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:20]([O:21][CH3:22])=[CH:19][C:12]2[NH:13][C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)C1C=CC=CC=1>CN(C=O)C.O>[CH2:25]([N:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]([O:21][CH3:22])=[CH:19][C:12]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCCC(=O)N2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CCCC(=O)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (297 mg, 1.0 mmol) and NaH (80 mg, 2 mmol) was stirred in DMF (5 mL) for 10 minute at rt and the appropriate benzyl bromide or benzyl chloride (1.1 mmol) added. The mixture was stirred o/n at rt. After addition of water the organics extracted with ethyl acetate, washed with water, brine, dried (MgSO4), filtered and concentrated. The crude yellow oil was purified by flash chromatography (hexane/EtOAc 1:0 to 1:1) and the resultant solid stirred in Et2O, filtered and dried under vacuum.