Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].I[C:9]1[C:10]([NH:15][C@@H:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=1.C1(C2C=CC=CC=2)C(O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:44]([CH3:51])=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>C1COCC1.[Cu]I>[CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:51][C:44]1[N:15]([C@@H:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:45]=1[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: C[C@@H](Nc1ncccc1I)C1CCOCC1
Reactant: CCOC(=O)C=C(C)O
Agent: [Cu]I
Agent: CC(C)(C)[S@@](N)=O
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n([C@H](C)C2CCOCC2)c2ncccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A re-sealable vial containing (S)- or (R)-3-iodo-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2-amine (0.333 g, 1.002 mmol), copper(I) iodide (0.0084 g, 0.044 mmol), biphenyl-2-ol (0.018 g, 0.106 mmol), and cesium carbonate (0.672 g, 2.062 mmol) was diluted with THF (3.5 mL). To the orange mixture was added ethyl 3-hydroxybut-2-enoate (0.25 mL, 1.977 mmol). The resultant blue-green contents were evacuated and purged with N2 (g) (3×). The vial was subsequently sealed and heated to 100° C. After 24 h, the reaction mixture was cooled to room temperature and filtered over a pad of Celite. The filter pad was washed with EtOAc (3×) and the filtrate was concentrated to give a thick brown oil. The resultant oil was purified on a Biotage system (50 g, gradient elution 2% EtOAc: 98% Hexanes to 15% EtOAc: 85% Hexanes, then 15% EtOAc: 85% Hexanes). The product (S)- or (R)-ethyl 2-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.257 g, 0.812 mmol, 81.0% yield) was isolated as a white foam. LRMS (M+H+) m/z: calcd 317.2. found 317.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[OH:11])=[O:3].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[C:5]([O:11][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(Cl)ccc3C(C)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
4-Chloro-2-hydroxyacetophenone (45 mg), 4-chloro-6,7-dimethoxyquinoline (60 mg), and 4-dimethylaminopyridine (95 mg) are suspended in o-dichlorobenzene (10 ml) to prepare a suspension which was then stirred at 120° C. overnight and then at 140° C. for 5 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (11 mg, yield 12%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 97 °C
Reaction time: 8 h

Procedure:
To a 125 mL 3 neck flask with mechanical stirring, condensers, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g -chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate. The mixture was slowly heated under nitrogen in an oil bath to 97° C. The reaction was allowed to proceed overnight. The mixture was cooled to ambient temperature and 40 mL deionized water was added to dissolve the solids. The aqueous layer was separated and discarded and the water wash repeated. 25 mL of 8N hydrochloric acid were added in a single aliquot to extract the intermediate. The layers were separated and the acidic aqueous layer returned to the reaction flask. The aqueous layer was heated to 95° C. and the reaction was allowed to proceed for 24 hours as a stress test. After 6 hours, 0.3% of ester remained. The mixture was cooled to 40° C. and 25 mL acetone was added. The mixture was cooled to 0° C.-5° C. for 1 hour. The filter cakes were rinsed with approx. 25 mL acetone and dried. HPLC revealed 0.2 g of product in filtrate. Yield (crystalline) 13.38 g (95.1% of theoretical).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[C:28]([F:31])([F:30])[F:29])[N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:3]2[S:4][C:5](=[CH:9][C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[C:28]([F:30])([F:31])[F:29])[N:14]=[CH:13]4)[C:6](=[O:8])[N:7]=2)[CH2:35][CH2:34]1
Reactant: CN1CCNCC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C#N)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C#N)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-{5-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-indazol-1-ylmethyl}-3-trifluoromethyl-benzonitrile was prepared from 4-[5-(2-methylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-indazol-1-ylmethyl]-3-trifluoromethyl-benzonitrile and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH:19]([CH3:21])[CH3:20])=[CH:7][C:8]2[O:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]=1[CH:16]([CH3:18])[CH3:17])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:4][C:5]1[C:6]([CH:19]([CH3:21])[CH3:20])=[CH:7][C:8]2[O:12][C:11]([CH3:13])([CH3:14])[CH2:10][C:9]=2[C:15]=1[CH:16]([CH3:17])[CH3:18]
Reactant: CC(=O)Oc1c(C(C)C)cc2c(c1C(C)C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(C(C)C)c1O)CC(C)(C)O2
Temperature: 25 °C
Yield: 63.8 %

Procedure:
Under argon atmosphere, 77 mg of 5-acetoxy-2,2-dimethyl-4,6-diisopropyl-2,3-dihydrobenzofuran was dissolved in 1 ml of anhydrous tetrahydrofuran, a solution of 25 mg of lithium aluminium hydride in 2 ml of anhydrous tetrahydrofuran was added, and the solution was stirred at room temperature for a whole day and night. After cooling to 0° C., the reaction was quenched with water and then the reaction mixture was extracted with a 10% aqueous hydrochloric acid solution and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 42 mg of 5-hydroxy-2,2-dimethyl-4,6-diisopropyl-2,3-dihydrobenzofuran as a light red solid (yield 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][NH:13][CH:14]3[CH2:16][CH2:15]3)[CH:11]=1)[O:8][C:7]([CH3:18])([CH3:17])[CH2:6][C:5]2([CH3:20])[CH3:19].[CH:21](OCC)=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH:14]3[CH2:15][CH2:16]3)[CH:21]=[O:22])[CH:11]=1)[O:8][C:7]([CH3:18])([CH3:17])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(CNC3CC3)c2O1
Reactant: CCOC=O
Product: CC1(C)CC(C)(C)c2cc(Br)cc(CN(C=O)C3CC3)c2O1
Yield: 100 %

Procedure:
A solution of 6-bromo-8-[(cyclopropyl-amino)-methyl]-2,2,4,4-tetramethyl-chroman (Intermediate 7, 1.4 g, 4.14 mmol) in ethyl formate was refluxed for 6 h. The solvent was distilled off in vacuo to afford the title compound as a clear oil (1.56 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([N:19]([CH2:30][C:31]([O:33]CC)=[O:32])[C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])=[O:18])[CH2:13][CH2:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([N:19]([CH2:30][C:31]([OH:33])=[O:32])[C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])=[O:18])[CH2:15][CH2:16]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)CN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)cc(N2CCN(C(=O)N(CC(=O)O)c3cc(C)c(C)cc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Ethyl 2-({[4-(3,5-dimethoxyphenyl)piperazino]carbonyl}-2-methoxy-4,5-dimethylanilino)acetate(200 mg, 0.41 mmole) was dissolved in dioxane:distilled water(4:1, 15 ml), lithium hydroxide monohydrate(50.7 mg, 1.23 mmol) was added thereto, and then the resulting mixture was stirred at room temperature for 3 hours, acidified with 1N-hydrochloric acid, extracted with ethylacetate, filtered to dryness, concentrated under the reduced pressure to remove the used solvent, and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4]Br.[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=2)[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH2:4][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=2)[CH:23]=[CH:22]1.[CH2:14]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][C:31]([OH:33])=[O:32])[CH:28]=2)[CH:23]=[CH:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3c(F)cccc3C(F)(F)F)c2c1

Procedure:
The titled compound (16 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-fluoro-6-(trifluoromethyl)benzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CC=CC=1.ClCCl>O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 5 %

Procedure:
A mixture of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.025 g, 0.08 mmol), benzyl chloroformate (0.016 g, 0.09 mmol), pyridine (0.50 ml) and dichloromethane (0.50 ml) was stirred at room temperature over the weekend and poured into water. The resulting precipitate was collected by filteration and purified by flash column chromatography on silica using ethyl acetate/n-heptane (9:1) as the mobile phase to give benzyl N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate as a white solid (0.002 g, 0.004 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (s, 1H), 8.13 (s, 1H), 7.74 (d, 1H), 7.34-7.45 (m, 6H), 7.10 (d, 1H), 7.02 (dd, 1H), 6.08 (broad, 2H), 5.16 (s, 2H), 5.08 (m, 1H), 3.86 (s, 3H), 2.11 (m, 2H), 1.91 (m, 4H), 1.69 (m, 2H); MH+458; TLC (ethyl acetate) Rf 0.32; RP-HPLC (Hypersil C18, 5 μm, 200 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min 1 ml/min) Rt 19.00 min.
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.S(/[CH:13]=[CH:14]\[C:15](=[O:17])[CH3:16])C#N>C(O)C>[SH:3][C:4]1[N:8]([CH3:9])[N:7](/[CH:13]=[CH:14]\[C:15](=[O:17])[CH3:16])[NH:6][N:5]=1
Reactant: Cn1nnnc1S
Reactant: CC(=O)/C=C\SC#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(=O)/C=C\N1NN=C(S)N1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-mercapto-1-methyltetrazole sodium salt hydrate (1.1 g., 0.008 mole) in aqueous ethanol (15 ml), a solution of cis-4-thiocyano-3-buten-2-one (Compound 28) in ethanol was added dropwise over 5 minutes. A solid suspension was observed forming over the next 2 hours which was stirred at 25° C. for 18 hours. The volatiles were removed in vacuo and the residue was extracted into ethyl acetate and washed thoroughly with water. After drying (MgSO4), the solution was concentrated. The solid residue was purified via column chromatography on silica gel using hexanes/ethyl acetate (3:2) as eluant to yield 1.1 g of a white solid, mp 112°-114° C. IR (nujol) uc=o 1660 cm-1.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:37]1CCCC1>>[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:19][CH2:20][CH2:21][OH:37])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCCCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (253 ml) was added dropwise, under nitrogen, a solution of 41.8 g of 4-benzyloxy-13-phenyl-1-tridecene in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 hours, quenched by the sequential addition of 72 ml of ethanol, 24 ml of 6 N solution of sodium hydroxide, and 48 ml of a 30% solution of hydrogen peroxide. The mixture was heated at 50° for 2.5 hours. Upon standing at room temperature overnight, the mixture separated into aqueous and organic layers. The organic layer was washed with 100 ml of a 10% aqueous solution of sodium sulfite and 100 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous potassium carbonate and concentrated. The concentrate was taken up in 20% diethyl ether/hexane, filtered and concentrated to an oil. The oil was purified by high pressure liquid chromatography using as an eluent hexane/diethyl ether (2:1 by volume) to give 32.7 g (75%) 4-benzyloxy-13-phenyl-tridecan-1-ol as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:28][CH3:29])=[C:15]([CH:27]=2)[C:16]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[O:17])=O)[CH:5]=[CH:4][N:3]=1.Cl[C:31]1[N:36]=[C:35](/[CH:37]=[C:38](\[C:40]2C=CC(OC)=C(C=2)C(NC2C(F)=CC=CC=2F)=O)/O)C=C[N:32]=1.C1C(=O)N(Br)C(=O)C1.NC1C=CC=CN=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:36]3[CH:35]=[CH:37][CH:38]=[CH:40][C:31]3=[N:32][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:28][CH3:29])=[C:15]([CH:27]=2)[C:16]([NH:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(C(=O)Cc2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1ccc(/C(O)=C\c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Nc1ccccn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 60 °C
Yield: 72 %

Procedure:
A tautomeric mixture of 5-[(2-Chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide and 5-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (1.26 g, 3.02 mmol) was dissolved in 60 mL of DCM with stirring. NBS (0.538 g, 3.02 mmol) was added in a single portion. The reaction was stirred for 20 minutes and concentrated in vacuo. The residue was dissolved in 60 mL of dioxane with stirring, and 2-aminopyridine (0.853 g, 9.06 mmol) was added in a single portion. The reaction was heated at 60° C. with an oil bath for 24 hours and cooled to rt. The reaction was stirred at rt for an additional 40 hours. The reaction was poured into half-saturated NaHCO3 solution and EtOAc, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. Impure fractions were concentrated and further purified by flash chromatography. The combined clean fractions (by TLC) from both runs were combined and concentrated in vacuo to afford 1.07 g (72%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 9.40 (d, J=7.0 Hz, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.84-7.77 (m, 2H), 7.57 (m, 1H), 7.39 (m, 1H), 7.33-7.26 (m, 2H), 7.24-7.14 (m, 3H), 3.99 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([S:14][CH2:15][CH3:16])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH3:24]>>[CH2:15]([S:14][C:7]1[CH:8]=[C:9]([CH:13]=[C:5]([S:2](=[O:4])(=[O:3])[NH2:24])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([OH:12])=[O:11])[CH3:16]
Reactant: CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Oc1ccccc1
Reactant: N
Product: CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
5-Chlorosulfonyl-3-ethylthio-4-phenoxybenzoic acid (1 g) is added to concentrated aqueous ammonia (20 ml) at 5°-10° C. After 30 minutes the reaction mixture is heated on a steam-bath for 1 hour while most of the excess of ammonia was allowed to distill off. After cooling, the precipitated ammonium salt of 3-ethylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is dissolved in hot water (75 ml) and the solution acidified by addition of hydrochloric acid. After cooling, the precipitated 3-ethylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the compound with a melting point of 225°-227° C after drying in vacuo at 80° C.
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)=S)([CH3:4])([CH3:3])[CH3:2].ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(N(CC)CC)C>[C:1]([N:5]=[C:6]=[N:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=S)Nc1cc(F)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)N=C=Nc1cc(F)cc(Cl)c1

Procedure:
To a solution of 1.04 g of N-t-butyl-N'-(3-chloro-5-fluorophenyl)thiourea produced in Example A-11 in 25 of dichloromethane were added 4.18 g of triphenylphosphine, 2.53 g of carbon tetrachloride and 1.61 g of triethylamine. The mixture was refluxed for 2 hours and evaporated in vacuo. The residue was chromatographed on a silica gel column using cyclohexane as a solvent to give N-t-butyl-N'-(3-chloro-5-fluorophenyl)carbodiimide as an oil. To a solution of this oil in 1.5 ml of DMF were added 500 mg of cyanamide and 0.1 ml of diisopropylethylamine. The mixture was stirred at 100° C. overnight, cooled to room temperature, poured into ice-water, and extracted with ethyl acetate. The extract was evaporated in vacuo to dryness and the residue recrystallized from isopropyl alcohol to give 0.1 g of the title compound as colorless needles melting at 156.0°-157.0° C.
Reaction SMILES: [N:1]([C:4]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[CH2:9])=[N+]=[N-]>C1C=CC=CC=1>[N+:20]([C:19]1[C:4]2[N:1]3[CH2:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[CH2:7][O:6][C:5]=2[CH:16]=[CH:17][CH:18]=1)([O-:22])=[O:21]
Reactant: C=C(COc1cccc([N+](=O)[O-])c1N=[N+]=[N-])c1ccccn1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccc2c1N1CC1(c1ccccn1)CO2
Temperature: 80 °C
Yield: 99.5 %

Procedure:
A mixture of 2-{1-[(2-azido-3-nitrophenoxy)methyl]vinyl}pyridine (250 mg, 0.84 mmol) in benzene (15 mL) was refluxed at 80° C. for 15 h. The reaction was concentrated to give the crude product. The product was purified by FCC on silica gel eluting with a hexane:ethyl acetate gradient to give 7-nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazine as a solid (0.225 g, 90%). LCMS calculated for C14H12N3O3 (M+H)+: m/z=270.1. found: 270.1.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([I:11])[C:3]=1[OH:12].[C:13]([CH:15]1[CH2:17][CH2:16]1)#[CH:14].O>N1C=CC=CC=1>[CH:15]1([C:13]2[O:12][C:3]3[C:4]([I:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[CH:14]=2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cc(I)c(O)c(I)c1
Reactant: C#CC1CC1
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1cc(I)c2oc(C3CC3)cc2c1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu2O (1.9 mg, 13.2 mmol) in 100 mL of dry pyridine was refluxed for 2 h. The reaction mixture was poured into 1 L of water and stirred for 10 min. The resulting mixture was filtered. The cake was purified by column chromatography on silica gel eluting with EtOAc/PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.47 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H), 1.14-1.04 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>>[C:34]([O:37][CH2:38][C:39]([N:31]1[CH2:32][CH2:33][CH:28]([C:25]2[N:24]=[C:23]([NH:22][C:10]3[C:9]([O:8][C:7]4[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:14][C:13]([S:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][N:11]=3)[S:27][N:26]=2)[CH2:29][CH2:30]1)=[O:40])(=[O:36])[CH3:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CCNCC2)ns1
Product: CC(=O)OCC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n2)CC1
Yield: 96.5 %

Procedure:
Following the procedure in Example 1, Step G, and using N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(piperidin-4-yl)-1,2,4-thiadiazol-5-amine (Example 193, step F; 150 mg, 0.314 mmol) and 2-chloro-2-oxoethyl acetate (42.9 mg, 0.314 mmol) provided 2-(4-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)-2-oxoethyl acetate (175 mg, 0.303 mmol, 96.5% yield).