Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]([C@@H:18]1[O:20][CH2:19]1)=[O:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[F:13][C:11]1[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:19][C@@H:18]([OH:20])[C:16]([O:15][CH3:14])=[O:17])[CH:12]=1
Reactant: Cn1c(=O)oc2cc(N)cc(F)c21
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7, 0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 ml) is stirred and heated at 90° C. overnight. The reaction mixture is diluted with ethyl actetate, washed with water and saline, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography (50% ethyl acetate/hexane) gives pure product as a white solid (0.98 g, 60%); MS for C12H13FN2O5 m/z 285 (M+H)+.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[S:18][C:17]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:16][CH:15]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:12]([C:14]1[S:18][C:17]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:16][CH:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a stirred solution of isopropylamine (66 mg, 1.12 mmol) in dioxane (5 mL) under argon and at room temperature was added trimethylaluminium (0.60 mL of a 2M solution in toluene, 1.20 mmol). After 1 h, a solution of 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) in dioxane (5 mL) was added and the reaction mixture warmed to 90° C. After 3 h, the reaction mixture was cooled, quenched with Seignettes's salt solution and water, then extracted with dichloromethane. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 3% methanol in dichloromethane) gave the title compound (68 mg, 69%) as a white solid. MS: m/e=358.1 [M+H]+.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=O.[CH2:13]([C:15]1([CH2:44][CH3:45])[C:18](=[O:19])[N:17]([C:20]([NH:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][CH3:26])=[O:21])[CH:16]1[O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=O)=[CH:37][CH:36]=1)[CH3:14].CN(C)CCN.C1C=CC=CC=1>C(Cl)Cl>[CH3:1][N:3]([CH3:4])[CH2:7][CH2:6][NH:5][C:39]([C:38]1[CH:42]=[CH:43][C:35]([O:34][CH:16]2[C:15]([CH2:44][CH3:45])([CH2:13][CH3:14])[C:18](=[O:19])[N:17]2[C:20]([NH:22][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH2:24][CH2:25][CH3:26])=[O:21])=[CH:36][CH:37]=1)=[O:41]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)O)cc1)c1ccc(C)cc1
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCC(NC(=O)N1C(=O)C(CC)(CC)C1Oc1ccc(C(=O)NCCN(C)C)cc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.104 g carbonyldiimidazole in 2 ml methylene chloride is added a solution of 0.227 g of [S-(R*,S*)]-4-((3,3-diethyl-1-((-1-(4-methylphenyl)butylamino)carbonyl)-4-oxo-2-azetidinyl)-oxy)benzoic acid in 3 ml methylene chloride. The mixture is stirred at ambient temperature for 30 minutes at which time 0.100 g of N,N-dimethylethylenediamine is added. After stirring overnight at room temperature the reaction mixture is poured into benzene (50 ml) and washed with water. The organic layer is separated, dried through sodium sulfate and concentrated in vacuo. Silica gel chromatography using 5% methanol in methylene chloride yields 0.160 g of 2-[4-[[[2-(dimethylamino)-ethyl]amino]carbonyl]phenoxy]-3,3-diethyl-N-[1-(4-methylphenyl)butyl]-4-oxo-1-azetidinecarboxamide. (Compound 73).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH3:32])[CH:22]=[N:23][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3[CH3:32])[CH:22]=[N:23][CH:24]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1cncc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 50.6 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylboronic acid (0.55 g, 2.0 mmol, Lancaster Chem Co.) and 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine (300 mg, 1.1 mmol) in toluene (5.0 mL) was added Pd(0) (25 mg) and Na2CO3 (1 mL of a 2 M solution), and the mixture was heated at reflux. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel to afford 225 mg of the title compound. MS (CI/NH3) m/z 405 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.83 (m, 3H), 2.08 (m, 1H), 2.36 (m, 1H), 2.54 (s, 3H), 2.78 (m, 1H), 3.17 (m, 1H), 4.10 (m, 2H), 7.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 7.92 (s, 1H), 8.00 (s, 2H), 8.42 (m, 1H), 8.48 (m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[O:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH3:24]>C(OCC)(=O)C.O>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[N:7]=[C:6]([NH:5][C:1](=[O:2])[NH:32][S:29]([O:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=2[O:25][CH2:23][CH3:24])(=[O:31])=[O:30])[N:11]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOc1ccccc1OS(N)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ethyl acetate (16 ml) was introduced and cooled to −10° C. under nitrogen. Phosgene (4.0 g, 0.04 mol) was passed in at this temperature and then a solution of 2-amino-4,6dimethoxypyrimidine (2.86 g, 0.0185 mol) and triethylamine (3.73 g, 0.037 mol) in ethyl acetate (20 ml) was added dropwise in the course of 2 h. After 1 h, the reaction was warmed to 20° C., nitrogen was blown through until there was no longer phosgene in the solution, and then a solution of 2-ethoxyphenoxysulfonamide (4.0 g, 0.0184 mol) in ethyl acetate (10 ml) and triethylamine (1.86 g, 0.0184 mol) in ethyl acetate (10 ml) were successively added dropwise in the course of 30 min. After 30 min, water (100 ml) was added, the phases were separated and the organic phase was extracted with 2×25 ml of 1.5M sodium hydroxide solution. The aqueous phases were combined, washed with xylene (20 ml), adjusted to pH=2 using 6M hydrochloric acid and the product was filtered off and dried; yield: 5.57 g, 70.7% of theory.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][CH2:8][C:9](O)=O>O>[NH2:5][C:3]1[S:4][C:9]([CH2:8][O:7][CH3:6])=[N:1][N:2]=1
Reactant: NNC(N)=S
Reactant: COCC(=O)O
Solvent: O
Product: COCc1nnc(N)s1

Procedure:
Addition of phosphonyl chloride to a mixture of thiosemicarbazide and methoxyacetic acid at 60°-95° and working up of the product yields 5-amino-2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 177°-179° (from water). When this compound is diazotised and treated with cuprous bromide 5-bromo-2-methoxymethyl-(1,3,4)-thiadiazole results and reaction of this bromo compound with zinc dust in acetic acid at room temperature yields 2-methoxymethyl-(1,3,4)-thiadiazole, m.p. 30.5°-32°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.[Br:20]Br>ClCCl>[Br:20][C:17]1[CH:16]=[N:15][N:14]2[C:9]([C:5]3[CH:4]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:8]=[CH:7][CH:6]=3)=[CH:10][CH:11]=[N:12][C:13]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: BrBr
Solvent: ClCCl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1

Procedure:
To a 0.01 mole sample of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of dichloromethane is added 0.01 mole of bromine. After standing, the mixture is worked up as for Example 15 to give the product as crystals, m.p. 138°-140° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([NH2:23])=[N:20][C:19]=2[CH:24]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([NH:23][CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])=[N:20][C:19]=2[CH:24]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: Nc1nc2cc(Cl)ccc2s1
Product: CC1(C)Oc2ccncc2C(Nc2nc3cc(Cl)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 5-chloro-benzothiazol-2-ylamine as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][O:13][C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:15]=2[O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].O1CCCC1.C(O)(C)C.[BH4-].[Na+]>O>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([NH:20][C:16]2[C:15]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=3)=[C:14]([O:13][CH2:12][CH2:11][O:10][C:7]3[N:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][N:6]=3)[N:19]=[CH:18][N:17]=2)(=[O:23])=[O:22])=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)=O)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)O)cn2)c1
Reaction time: 0.67 h
Yield: 75.3 %

Procedure:
To a mixture of N-[6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (756 mg), tetrahydrofuran (10 ml) and isopropyl alcohol (10 ml) is added with stirring sodium borohydride (48 mg) under ice-cooling, and the mixture is stirred for 40 minutes under ice-cooling. To the reaction solution is further added sodium borohydride (14 mg), and the mixture is stirred for 30 minutes. The mixture is diluted with water, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=40:1~20:1), and recrystallized from ethyl acetate/n-hexane to give 4-tert-butyl-N-[6-{2-(5-(1-hydroxyethyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (571 mg) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][NH:11][CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1.C(Cl)Cl>[CH3:10][N:11]([CH2:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CNC
Reactant: O=Cc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1cccc(O)c1

Procedure:
3-Hydroxybenzaldehyde (1.0 g), 2M dimethylamine in THF (5 mL), and sodium triacetoxyborohydride (2 g) in CH2Cl2 (10 mL) were stirred for 24 hours. The mixture was treated with methanol and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1C=CC=CC=1.O>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:28])=[CH:30][CH:31]=1)([O-:22])=[O:21]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
A 19.35 g. portion of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane is dissolved in 150 ml. of benzene. A 10.59 g. portion of sodium carbonate in 100 ml. of water is added with stirring. An 18.45 g. portion of p-nitrobenzoyl chloride in 100 ml. of benzene is added slowly to the rapidly stirred mixture. The mixtue is stirred for 1 hour and then allowed to stand overnight at room temperature. The product is recovered by filtration, washed successively with dilute sodium carbonate, 0.5N hydrochloric acid and then water and dried yielding the product as a white solid, mp 177°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:18][OH:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11](/[C:12](/[NH2:13])=[N:18]/[OH:19])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: NO
Solvent: CCO
Product: COc1ccc(Oc2ccc(/C(N)=N/O)cc2)cc1

Procedure:
4-(4-Methoxyphenoxy)benzonitrile (581 mg, 2.58 mmol) was dissolved in ethanol (10.0 mL) and hydroxylamine (630 μL, 10.32 mmol) was added. The mixture was refluxed for 1 hour and the reaction was cooled and then concentrated in vacuo to give the crude product which was taken to the next step without further purification (636 mg, 95%). 1H NMR (500 MHz, CDCL3) δ(ppm): 3.81 (1H, s), 4.87 (1H, bs), 6.88-6.94 (4H, m), 6.99 (2H, d, J=9.2 Hz), 7.55 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 55.8 (CH3), 115.2 (CH), 117.4 (CH), 121.4 (CH), 126.6 (CH), 127.6, 149.5, 152.5, 156.5, 160.4. MS (FAB+): 259 (MH+). HRMS for C14H14N2O3 (MH+): calculated: 259.1083; found 259.1100.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 6-Chloro-nicotinic acid (3.00 g, 19.0 mmol) in 30 mL dimethylformamide was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (10.9 g, 20.9 mmol), 1-methylpiperazine (2.30 g, 22.1 mmol), and triethylamine (2.18 g, 21.5 mmol). After stirring for 18 hours, this was partitioned between ethyl acetate and water. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (elution with 3% methanol/dichloromethane) to yield (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.50 g, 9.33 mmol).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[Na+].[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28](=[O:31])[CH2:29][CH3:30])[N:21]=2)[N:19]=1>CC(C)=O>[C:1]([NH:12][C:11](=[S:10])[NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28](=[O:31])[CH2:29][CH3:30])[N:21]=2)[N:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(=O)NCc1cccc(-c2csc(N)n2)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)n1
Yield: 84.8 %

Procedure:
Benzoyl chloride (7.7 g) was added slowly to a solution of sodium thiocyanate (4.8 g) in acetone (220 ml) under refluxing and the mixture was refluxed for 15 minutes. 2-Amino-4-(6-propionylaminomethylpyridin-2-yl)thiazole (12.0 g) was added to the mixture. The mixture was refluxed for 4 hours. The resulting precipitate was collected by filtration and was washed with water and then acetone to afford 2-(3-benzoylthioureido)-4-(6-propionylaminomethylpyridin-2-yl)thiazole (16.5 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCl.[S:12](=O)(=[O:15])([OH:14])[OH:13].C(C(CCCC)C([O-])=O)C.[K+:27]>C(OCC)(=O)C>[K+:27].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:12]([O-:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 77.9 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and dichloromethane (30 mL), was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 30-40° C. then stirred for 1-2 h. The reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)/[C:7](/Cl)=[N:8]/[OH:9].[CH2:13]([Cl:16])[CH:14]=[CH2:15].Cl.O>CCOCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:7]2[CH2:15][CH:14]([CH2:13][Cl:16])[O:9][N:8]=2)[CH:11]=1
Reactant: O/N=C(\Cl)c1cc(Br)ccc1F
Reactant: C=CCCl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(Br)cc1C1=NOC(CCl)C1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
TEA (0.551 ml, 3.96 mmol, Aldrich) was added drop wise to a stirred solution of (Z)-5-bromo-2-fluoro-N-hydroxybenzimidoyl chloride (1c, 1 g, 3.96 mmol) at 0° C., followed by a solution of allyl chloride (0.968 ml, 11.88 mmol, Aldrich) in Et2O (20 mL). The reaction mixture was allowed to stir at RT for 4 hs. 2 M HCl (10 mL) was added, followed by water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with a gradient of 3% to 35% EtOAc in hexane, to provide the title compound as colorless oil (0.604 g, 2.065 mmol, 52.1% yield). MS m/z=293.9 [M+H]+. Calculated for C10H8BrClFNO 292.53.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[NH:7].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.Cl>[ClH:1].[ClH:1].[C:14]1([CH2:13][N:20]2[CH2:25][CH2:24][C:23]3([N:7]=[C:6]([NH2:8])[C:5]4[C:4](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:3]3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: N=C(N)c1ccccc1N
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(Cc3ccccc3)CC2)Nc2ccccc21

Procedure:
A solution of 2-aminobenzamidine dihydrochloride (2.0 g, 9.6 mmol) and N-benzyl4-piperidone (2.1 ml, 11.5 mmol) in ethanol (40 ml) and HCl (1M in Et2O, 5 ml) was heated at 70° C. for 20 h. Evaporation and flash column chromatography on untreated alumina eluting with DCM/methanol (10:1) gave after trituration from ether a yellow solid, MS (+EI) 307 ([M+H]+), 1H NMR (d6 -DMSO) 9.99 (1H, s), 9.1 (1H, s), 8.5 (1H, s), 7.81 (1H, d), 7.53 (1H, s), 7.46 (1H, t), 7.2-7.4 (5H, m), 6.89 (1H, d), 6.79 (1H, dd), 3.52 (2H, s), 2.4-2.6 (4H, m), 1.91 (2H, m), 1.82 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[C:19]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=4)=[S:34])=[CH:7][CH:6]=3)[CH:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3cc(-c4ccccc4)c4ccccc4n3)cc2)ccc1Cl
Yield: 60.7 %

Procedure:
2-(4-aminophenylthio)-4-phenylquinoline (3.0 mmoles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.3 mmoles, 0.79 g) were reacted according to procedure C to yield the title compound 1.03 g, 61%. Mass Spec (FD) 565. Calculated for C29H19ClF3N3 S2 : C, 61.53; H, 3.38; N, 7.42. Found: C, 61.82; H, 3.63; N, 7.43.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9])=C.Cl.O1CCOCC1>CO.C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NOCCO)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (57.0 mg, 0.109 mmol) in anhydrous MeOH (5.5 mL) and anhydrous THF (2.7 mL) under N2 was added 4 M HCl in dioxane (817 μL, 0.327 mmol, 3.0 eq), and the reaction mixture was stirred at room temperature. After 1 h the solvent was removed in vacuo and the residue was redissolved in acetonitrile (2.0 mL) and loaded onto Phenomenex Strata-X cartridge (5 g). The cartridge was washed with water (10 mL) and methanol (15 ml). The desired product was then eluted using 2M ammonia in MeOH. Trituration from DCM-hexane afforded the title compound as a tan solid (32.9 mg, 60.8%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 8.32 (d, J=5.9 Hz, 1H), 7.70-7.41 (m, 3H), 7.20 (dd, J=8.50 Hz, 1H), 6.26 (t, J=9.6 Hz, 1H), 4.78 (br s, 1H), 3.87 (dd, J=6.31 Hz, 2H), 3.70-3.39 (m, 3H), 1.27 (br s, 1H), 1.18-1.03 (m, 2H), 0.90-0.67 (m, 2H); LC-MS (method C): [M+H]+=497.0, RT=0.57 min.