Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(C(C)C)C(C)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:32])[C:29](Cl)=[O:30])=[CH:20]1>CN(C=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:29](=[O:30])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][CH:20]=1)=[O:32])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1NC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirring solution of 2-ethyl-aniline (74 μL, 0.6 mmol) and DIEA (110 μL, 0.6 mmol) in DMF (1 mL) was added a solution of (1H-indol-3-yl)-oxo-acetyl chloride (62 mg, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 2 hours, then filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product N-(2-ethyl-phenyl)-2-(1H-indol-3-yl)-2-oxo-acetamide (34 mg, 39%). HPLC ret. time 3.50 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.14 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.30 (m, 1H), 7.57 (m, 2H), 7.33-7.21 (m, 5H), 2.67 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H); ESI-MS m/z 293.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:13]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].O>[C:20]([O:19][CH:13]([C:3]1[S:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:6][C:2]=1[C:32]1[CH:41]=[CH:40][C:39]2[O:38][CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(OC(C)(C)C)c1sc(-c2ccccc2)cc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(OC(C)(C)C)c1sc(-c2ccccc2)cc1-c1ccc2c(c1)CCCO2
Temperature: 95 °C
Yield: 81.8 %

Procedure:
A solution of ethyl 2-(3-bromo-5-phenylthiophen-2-yl)-2-(tert-butoxy)acetate (10d) (86 mg, 0.22 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (101 mg, 0.39 mmol) and sodium carbonate (92 mg, 0.87 mmol) in a mixture of toluene (1.26 mL), ethanol (0.6 mL) and water (0.5 mL) was bubbled with nitrogen for 5 minutes. Palladium tetrakis(triphenylphosphine) (12 mg, 0.01 mmol) was added and the reaction mixture was heated at 95° C. overnight. After cooling to room temperature, water (2 mL) was added. The aqueous layer was extracted with toluene (2×8 mL). The organic layers were washed with brine (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to provide the desired product (10e) (80 mg, 0.18 mmol, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.ClC1C=CN=C2C=C(C3SC=CN=3)SC=12.BrC1SC=CN=1.Br[C:46]1[N:47]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:48]=[CH:49][N:50]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:46]3[N:47]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:48]=[CH:49][N:50]=3)[S:10][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccnc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Agent: Brc1nccs1
Agent: Clc1ccnc2cc(-c3nccs3)sc12
Product: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Cl)c2s1

Procedure:
Starting from the compound 98 (scheme 19) and following the procedure described above for the synthesis of compound 10 (example 12, scheme 2) but substituting 2-bromothiazole in the step 2 for the bromide 108, title compound 109 was obtained as a white solid (22 mg, 41% yield). MS (m/z) 366.1/368.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:8])=[C:3]([CH3:7])[CH2:4][CH2:5][OH:6].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C>O1CCCC1>[CH3:9][S:10]([O:6][CH2:5][CH2:4][C:3]([CH3:7])=[C:2]([F:8])[F:1])(=[O:12])=[O:11]
Reactant: CC(CCO)=C(F)F
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CCOS(C)(=O)=O)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To 100 ml of tetrahydrofuran, 4.45 g (36 mmol) of 4,4-difluoro-3-methyl-3-butenol and 4.59 g (40 mmol) of methanesulfonyl chloride were dissolved, followed by drop-wisely adding 4.42 g (44 mmol) of triethylamine under ice-cooling. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour. Hydrochloric acid salt of triethylamine was filtered, followed by adding water to the filtrate and extracting with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure to obtain 7.20 g (yield: 99%) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]#[N:15].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[F:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]3[NH:22][N:21]=[N:20][N:15]=3)=[C:2]([NH2:1])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1sc(-c2ccc(F)cc2)cc1N
Solvent: Cc1ccccc1C
Product: Nc1cc(-c2ccc(F)cc2)sc1-c1nnn[nH]1
Reaction time: 3 h

Procedure:
The mixture consisting of 0.65 g of 3-amino-2-cyano-5-(4-fluorophenyl)thiophene, 7.5 ml of xylene and 0.93 g of trimethyltin azide is stirred at 130–140° C. for 3 hours. Afterwards, the mixture is concentrated at 40° C. under reduced pressure and the residue is stirred with water with the addition of 1% trifluoroacetic acid. The precipitate is filtered off with suction and dried at 40° C. under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH3:3]C1C=CNN=1.[N:9]1[C:14]2[NH:15][C:16]3[CH:41]=[CH:40][CH:39]=[CH:38][C:17]=3[N:18]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][C:30]([CH3:33])=[N:29]4)=[CH:24][C:23]=3[C:34]([F:37])([F:36])[F:35])=[O:21])[CH2:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.CI>CCCCCC>[CH3:3][N:15]1[C:16]2[CH:41]=[CH:40][CH:39]=[CH:38][C:17]=2[N:18]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][C:30]([CH3:33])=[N:29]3)=[CH:24][C:23]=2[C:34]([F:37])([F:36])[F:35])=[O:21])[CH2:19][C:13]2[CH:12]=[CH:11][CH:10]=[N:9][C:14]1=2
Reactant: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Nc4ccccc43)c(C(F)(F)F)c2)n1
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4N(C)c4ccccc43)c(C(F)(F)F)c2)n1
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
Sodium hydride (60% suspension in oil, 0.12 g, 3.0 mmol) was washed with hexane, dried under nitrogen and resuspended in dry dimethylformamide (20 mL). Neat 3-methylpyrazole (0.13 mL, 1.61 mmol) was added dropwise at ambient temperature. Stirring was continued until the gas evolution subsided, and then the (5,11-dihydro-pyrido [2,3-b][1,5]benzodiazepin-6-yl)-(4-fluoro-2-trifluoromethyl-phenyl)methanone of Example 4, Step B (0.52 g, 1.34 mmol) was added in one portion to the clear solution. The mixture was placed in an oil bath (preheated at 130° C.) for 30 minutes. After cooling, sodium hydride (60% suspension in oil, 0.080 g, 2.0 mmol, washed with hexane) and methyl iodide (0.25 mL, 4.0 mmol) were added. The reaction mixture was stirred for an additional 15 minutes, and then partitioned between water and ethyl acetate. The organic extracts were dried over sodium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided the title product (0.28 g, 45.1%) as a foam which crystallized by sonication from ethanol-hexane as a white solid, m.p. 188-190° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:29])[C@@H:10]([OH:28])[CH2:11][N:12]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:13][C:14]([F:17])([F:16])[F:15])C1C=CC=CC=1.CC(O)=O.CCOCC>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH3:29])[C@@H:10]([OH:28])[CH2:11][N:12]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: C[C@H]([C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](N)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Reaction time: 72 h
Yield: 7.9 %

Procedure:
Pd(OH)2 was carefully wetted down under N2 with 20 mL of MeOH and the product of Step d (3.78 g) dissolved in 50 mL of MeOH was added followed by 70 mL of HOAc. The mixture was hydrogenated for 3 days on a Parr shaker at 50 PSI. Worked up by filtering off the catalyst under N2 and vacuum through a fiberglass filter paper to obtain an oil. To the oil was added Et2O/saturated NaHCO3 (100 mL) The layers were separated. The aqueous was basified further with 1N NaOH to pH=12 then extracted 3 times with Et2O. The Et2O extracts from the 1N NaOH layer were combined, dried (Na2SO4) and stripped to give 2.46 g of and amber oil. The oil was purified by flash chromatography in 9:1 Hexanes/EtOAc to 100% EtOAc. Obtained 192 mg of an oil. MS (ESI) detects (M+H)+=323.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[NH:13]([CH2:20][CH2:21][C:22]#[N:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>CS(C)=O.CO.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:21](=[CH:20][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]#[N:23]
Reactant: N#CCCNc1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: N#CC(=CNc1ccccc1)Cc1ccc2ccccc2c1

Procedure:
To a mixture of 2-naphthaldehyde (4.69 g, 30 mmol) and beta-anilinopropionitrile (4.82 g, 33 mmol) in dimethyl sulfoxide (35 ml) was added potassium t-butoxide (3.70 g, 33 mmol). The solution immediately turned a dark red. It was heated at 100° for 30 minutes, cooled, and diluted with methanol (15 ml) and water (25 ml). A copious yellow precipitate formed, which was chilled and isolated. The precipitate, 2-(2-naphthylmethyl)-3-anilinoacrylonitrile, was washed with dilute methanol and hexane; yield, 7.65 g. A portion was recrystallized from absolute ethanol; m.p. 148°-153° C. Anal. Calcd. for C20H16H2 : C, 84.48; H, 5.67; N, 9.85. Found: 84.38; H, 5.69; N, 9.82.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH:18]=[C:17]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCNCC4)on3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C4CCN(CCCCO)CC4)on3)ccc21

Procedure:
The preparation was carried out as already described starting from 130 mg of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)isoxazol-5-yl]piperidine and 83 μl of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].Cl[C:9]([O:11][CH3:12])=[O:10]>ClCCl.N1CC=CC1>[CH3:12][O:11][C:9]([N:3]1[CH2:4][CH:5]=[CH:2][CH2:1]1)=[O:10]
Reactant: COC(=O)Cl
Reactant: CCN(CC)CC
Agent: C1=CCNC1
Solvent: ClCCl
Product: COC(=O)N1CC=CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In dichloromethane (20 ml), 3-pyrroline (1.1 ml) was dissolved, followed by the addition of triethylamine (2.6 ml) and methyl chloroformate (1.2 ml) under ice cooling. The resulting mixture was stirred at room temperature for 17 hours. The residue obtained by distilling the reaction mixture under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (0.95 g, 52%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[C:4]2[C:19](O[C:22](=[O:23])[C:3]=12)=[O:20].[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CO>[NH2:18][C:5]1[C:4]2[C:19](=[O:20])[N:32]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:22](=[O:23])[C:3]=2[C:2]([NH2:1])=[C:15]2[C:14](=[O:16])[C:13]3[C:8]([C:7](=[O:17])[C:6]=12)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: CCCCCCCCN
Reactant: Nc1c2c(=O)oc(=O)c2c(N)c2c(=O)c3ccccc3c(=O)c12
Solvent: CO
Product: CCCCCCCCn1c(=O)c2c(N)c3c(=O)c4ccccc4c(=O)c3c(N)c2c1=O

Procedure:
(B-Cyan-4) Synthesis of 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye. To 120 grams of 15 percent oleum (fuming sulfuric acid having 15 percent sulfur trioxide), 10.0 grams of 1,4-diamino anthraquinone-2,3-dinitrile were added at 30° C. and the mixture stirred for two hours. This reaction mixture was poured into 1,000 grams of ice water and the precipitates were filtered. The wet precipitates were added to 400 grams of cooled water and dissolved by the addition of sodium hydroxide, followed by adjusting pH to 12.5. The temperature was now raised to 100° C. and maintained for two hours. After that period, 20 grams of 50 percent sulfuric acid were added to the mixture and heating was continued for another one hour. The precipitate of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride thus obtained was collected by filtration, washed with water and dried. 3.2 Grams of 1,4-diamino anthraquinone-2,3-dicarboxylic acid anhydride (0.01 mole), 3.2 grams (0.025 mole) of n-octyl amine, and 50 milliliters of methanol were added to a 100 milliliter round-bottom flask equipped with a condenser and the contents refluxed for a period of 24 hours. The reaction mixture was cooled, filtered and washed twice with methanol (100 milliliters each time). The reaction product was dried in air to obtain 4,11-diamino-2-n-octyl-1H-naphth[2,3-f] isoindole-1,3,5,10(2H)-tetrone cyan dye.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH:13]=1)=[O:10])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])nc1
Yield: 62.4 %

Procedure:
A solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxy-4-methylphenyl)benzamide (8.35 g, 28.4 mmol), 5-bromo-2-nitropyridine (5.24 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6 mmol) in N,N-dimethylformamide (70 mL) was stirred at 60° C. for 4 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→60/40), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (6.70 g, 63%) as a yellow amorphous solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[S:26][CH:27]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd]Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH3:22][C:23]1[CH:24]=[C:25]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[S:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1csc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (Compound 1061, 2.65 g, 8 mmol, prepared according to the procedure described in Organic Letters, 3(15), pp. 2317-2320, 2001), 4-methylthiophene-2-boronic acid (1.14 g, 8 mmol), and sodium bicarbonate (1.01 g in 10 mL water, 12 mmol) in DMF (30 mL) was degassed with a nitrogen stream for 20 minutes. To the mixture was added tris(diphenylphosphinoferrocene) dichloropalladium (584 mg, 0.8 mmol) and the reaction was stirred for 10 minutes at 120° C. under microwave irradiation. The crude mixture was diluted with ethyl acetate and washed successively with water (2×15 mL) and brine (1×15 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography to afford 1.67 g of tert-butyl 4-(4-methylthiophen-2-yl)piperidine-1-carboxylate (Compound 1062) as a yellow oil; ESMS (M+H)=224.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:24]1[C@@H:28]([C:29]([NH2:31])=[O:30])[NH:27][CH2:26][C@H:25]1[F:32].Cl.CCN(C(C)C)C(C)C>>[F:32][C@@H:25]1[CH2:26][N:27]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:28]([C:29]([NH2:31])=[O:30])[CH2:24]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@@H](F)C[C@H]3C(N)=O)cc1OCC2
Yield: 22 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and 4-cis-fluoro-L-prolinamide hydrochloride with added DIPEA (2.2 eq.), were reacted and the crude product recrystallised from IMS to give 373 as a white solid (56 mg, 22%). LCMS: RT=2.59 min, [M+H]+=427. 1H NMR 400 MHz (DMSO-d6) δ: 9.05 (1 H, s), 7.84 (1 H, d, J=0.63 Hz), 7.80 (1 H, s), 7.11 (1 H, s), 6.92 (1 H, s), 5.93-5.91 (2 H, m), 5.42 (1 H, s), 5.29 (1 H, s), 4.46-4.44 (5 H, m), 3.83-3.54 (2 H, m), 2.28 (1 H, dd, J=20.28, 14.80 Hz), 1.43 (6 H, dd, J=6.59, 3.60 Hz)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13].Cl[C:15]1[C:20]([Cl:21])=[C:19]([CH2:22][CH3:23])[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1>CCOCC.O>[Cl:21][C:20]1[C:15]([NH:13][CH2:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:16][CH:17]=[N:18][C:19]=1[CH2:22][CH3:23]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: NCCc1ccc2ccccc2c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ncnc(NCCc2ccc3ccccc3c2)c1Cl

Procedure:
The product of Step A (0.68 g, 4.0 mmole) and 4,5-dichloro-6-ethylpyrimidine (0.71 g, 4.0 mmole) were dissolved in triethylamine (1.1 mL, 8.0 mmole) and toluene (7 mL) and heated to reflux for 4 hours. After cooling, the reaction mixture was treated with 20 mL of water and 30 mL of ether, partitioned, and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4), concentrated and chromatographed on silica gel with 10% ethyl acetate/hexane. The title compound was obtained as a white solid (0.77 g, 62% yield) , mp 81°-83° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C(=O)(O)[O-].[Na+].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(OC)(C)C.O>[CH3:6][N:5]([CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])[C:21](=[O:22])[CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNCC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COC(CN(C)C(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a 20 L Morton flask was added MTBE (5.52 L, 7 volumes) and (N-methyl-amino)-acetaldehyde dimethyl acetal (614 g, 5 mol) to form a solution at room temperature. A solution of sodium bicarbonate prepared by the addition of sodium bicarbonate (546 g, 6.5 mol) and water (6.31 L, 8 volume) was added to the Morton reaction flask. The mixture was cooled to less than 10° C and a MTBE (789 mL) solution of phenylacetyl chloride (789 g, 5 mol) was added dropwise to the cooled reaction mixture over a 1 h period. After addition, the reaction mixture was stirred at room temperature for 1 h. At this stage an HPLC analysis indicated that the reaction was completed. Extractive workup with MTBE (4 volumes), anhydrous magnesium sulfate drying followed by concentration on the rotary evaporator provided 1.187 kg (98%) of N-methyl-N-(2,2-dimethoxyethyl)phenylacetamide as a liquid, (M+H)+=237.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(Cl)Cl>[Br:33][CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1CBr
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a solution of (5-Fluoro-2-nitrophenyl) methanol (0.3 g, 1.75 mmol) in methylene chloride (5 mL0 was added triphenylphosphine (0.52 g, 2.01 mmol) and carbon tetrabromide (0.66 g, 2.01 mmol). After 3 hours, the reaction was concentrated and chromatographed using 3:1 hexane:ethyl acetate as eluant to provide 0.38 g (93%) of the desired product as white crystals. mp 38-41° C. Anal Calc'd for C7H5N3O2FBr: C, 35.93; H, 2.15; N, 5.99. Found: C, 35.97; H, 2.12; N, 5.91.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[Cl:16][C:17]1[S:21][C:20]([S:22]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][N:2]([CH3:15])[CH3:1])[C:6]2=[O:14])(=[O:24])=[O:23])=[CH:19][CH:18]=1
Reactant: CN(C)CCn1c(=O)[nH]c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2ccc(Cl)s2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[2-(dimethylamino)ethyl]-1,3-dihydrobenzimidazol-2-one (20 mg, 0.1 mmol) in THF at room temperature is treated with (5-chlorothien-2-yl)sulfonyl chloride (26 mg, 0.12 mmol) followed by diisopropylethylamine (25 uL, 0.2 mmol) and dimethylaminopyridine (5 mg), stirred at room temperature for 16 hours and concentrated in vacuo. The resultant residue is dissolved in a mixture of dimethylsulfoxide, methanol and water and purified by Gilson1 preparative HPLC to give the title product, 16 mg, [M+H] 386, retention time (RT) 2.83 minutes. 1Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B:0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.