Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6](SC)[C:5]=1[F:15].[S:16](=[O:20])(=O)(O)[OH:17].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C:30](O)(=O)C>>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:16]([CH3:30])(=[O:20])=[O:17])[C:5]=1[F:15]
Reactant: CC(=O)O
Reactant: O=S(=O)(O)O
Reactant: CSc1c(C(=O)O)ccc(Cl)c1F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Temperature: 80 °C

Procedure:
Hydrogen peroxide (30%; 66 ml) was added to a suspension of 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (2.5 g) and concentrated sulphuric acid (1.5 ml) in acetic acid. The mixture was heated slowly to 80° C. and stirred and heated at that temperature overnight. It was cooled to room temperature and treated with sodium metabisulphite (45 g). It was evaporated and the residue was treated with water and acidified to pH 1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (24 g) as an off white solid m.p. 196°-200° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17]>C(O)(=O)C.N1CCCCC1.C(=O)CCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:6][CH2:5][CH2:4][CH2:9][CH3:8])[S:13][C:12]1=[S:17]
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Solvent: CCCCC=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCCC=C1SC(=S)N(N=c2sc3ccccc3s2)C1=O
Yield: 89.6 %

Procedure:
A slurry of 2.0g of 3-[(1,3-benzodithiol-2-ylidene)amino]- 2-thioxo-4-thiazolidinone (see example 37), valeraldehyde (10 ml, excess) and acetic acid/piperidine (2:1) (10 drops) in anhydrous slyme (400 ml) is heated at reflux for eighteen hours. The reaction mixture is chilled in an ice bath and the resultant precipitate collected by filtration. This precipitate (1.6 g) is recrystallized from 50 ml of dimethylformamide to yield 1.1 g of the title compound, melting point 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[H-].[Na+].[CH3:17]I>CN(C)C=O.O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:17])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1
Reactant: CCc1nc(Cl)c2c(n1)OCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(Cl)c2c(n1)OCC(=O)N2C

Procedure:
To a stirred suspension of 5g (0.023 mole) of 4-chloro-6,7-dihydro-2-ethyl-5H-pyrimido[4,5-b][1,4]oxazin-6-one (prepared using the method of Melik-Ogandzhanyan, et al., Khimiya Geterotsiklicheskikh Soedinenii, 1985, 974) in 100 ml of N,N-dimethylformamide was added 0.75g (0.025 mole) of 80% sodium hydride in oil. After ten minutes 3.5g (0.025 mole) of methyl iodide was added. After two hours the solution was diluted with about 400ml of water, and extracted thrice with 250ml portions of chloroform. The extracts were washed with water, dried over magnesium sulfate, treated with decolorizing charcoal, and evaporated in vacuo. The resulting oil was triturated with a mixture of diethyl ether and hexanes to provide light green solid 4-chloro-6,7-dihydro-2-ethyl-5-methylpyrimido[4,5-b][1,4]oxazin-6-one.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.[OH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[F:31][C:32]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:33]=1[O:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]2[N:46]=[C:45]3[CH2:47][NH:48][CH2:49][CH2:50][C:44]3=[N:43][C:42]=2[NH:51][CH:52]([CH3:54])[CH3:53])[CH2:37][CH2:36]1.C=O>CO>[F:31][C:32]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:33]=1[O:34][CH:35]1[CH2:36][CH2:37][N:38]([C:41]2[N:46]=[C:45]3[CH2:47][N:48]([CH3:1])[CH2:49][CH2:50][C:44]3=[N:43][C:42]=2[NH:51][CH:52]([CH3:54])[CH3:53])[CH2:39][CH2:40]1.[C:25]([OH:26])([C:27]([F:30])([F:29])[F:28])=[O:24]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C)C4)CC2)c(F)c1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (22.3 mg, 0.105 mmol) was added to a mixture of DIPEA (18 μL, 0.105 mmol), 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (27.9 mg, 0.053 mmol) and formaldehyde (4 μL, 0.053 mmol) in MeOH (550 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (27.9 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.3 Hz, 6H), 1.88-1.98 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.05 (m, 3H), 3.07 (br s, 4H), 3.33-3.40 (m, 2H), 3.41-3.69 (m, 2H), 3.75 (s, 3H), 4.15-4.32 (m, 3H), 4.32-4.39 (m, 1H), 6.66 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.73 (dd, J=12.8, 2.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)(=[O:3])[CH3:2].C([O:18][N:19]=O)(C)(C)C.CC(C)([O-])C.Cl>C1COCC1.CCOC(C)=O.O>[CH:10]([N:8]1[C:7](=[O:13])[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[N:19][OH:18])=[N:9]1)([CH3:11])[CH3:12]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)c1ccc(=O)n(C(C)C)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1nc(C(=O)C=NO)ccc1=O
Temperature: 0 °C

Procedure:
A mixture of 6-acetyl-2-isopropyl-3(2H)-pyridazinone (74.0 g) and t-butylnitrite (73.3 ml) in THF (740 ml) was stirred at 0° C. Pottasium t-butoxide (55.3 g) was added to the reaction mixture. Then the reaction mixture was stirred at 25° C. for 1 hour. Water, 1N HCl and EtOAc were added to the reaction mixture. The organic layer was washed with 1N HCl, aq. NaHCO3 and brine. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain (1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)(oxo)-acetaldehyde oxime (15.0 g) as white powder.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH2:28][O:27][CH3:26])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (34.2 mg, 60.3%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.136 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C[Si]([O:36][S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])(C)C.Br[C:48]1[CH:56]=[CH:55][C:51]([N:52]([CH3:54])[CH3:53])=[CH:50][CH:49]=1.[Mg].[Cl-].[NH4+]>C(Cl)Cl.C1COCC1>[C:43]1([CH3:46])[CH:42]=[CH:41][C:40]([S:37]([O-:39])(=[O:36])=[O:38])=[CH:45][CH:44]=1.[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S+:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)[C:48]2[CH:56]=[CH:55][C:51]([N:52]([CH3:54])[CH3:53])=[CH:50][CH:49]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O[Si](C)(C)C)cc1
Reactant: CC(C)(C)Oc1ccc(S(=O)c2ccc(OC(C)(C)C)cc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)c1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A solution of 8.5 grams (0.025 mol) of bis(4-tert-butoxyphenyl) sulfoxide in 300 grams of methylene chloride was cooled in an ice water bath. To the solution, 1.3 grams (0.013 mol) of triethylamine was added and 12.2 grams (0.05 mol) of trimethylsilyl-p-toluenesulfonate was added dropwise in a controlled manner so that the temperature might not exceed 10° C. The reaction solution was ripened for 30 minutes while maintaining a reaction temperature of 0° to 10° C. A Grignard reagent, which was separately prepared in a conventional manner using 10.0 grams (0.05 mol) of 4-bromo-N,N-dimethylaniline, 1.2 grams (0.05 mol) of magnesium and 50 grams of THF, was added dropwise to the reaction solution in a controlled manner so that the temperature might not exceed 10° C. The reaction solution was ripened for 30 minutes while maintaining a reaction temperature of 0° to 10° C. 200 grams of an aqueous solution of 20% ammonium chloride was added to the reaction solution to terminate reaction. After separation, 200 grams of chloroform was added to the organic layer. After the organic layer was washed twice with 200 grams of water, the solvent was distilled off in vacuum, yielding an oily residue. The oily residue was recrystallized, isolating 7.6 grams (yield 49%) of bis(4-tert-butoxyphenyl)(4-dimethylaminophenyl)sul fonium p-toluenesulfonate with 99% purity.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:26](O)=O)[C:20]=2[N:19]=[CH:18]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:26]([C:25]2[C:20]3[N:19]=[CH:18][NH:17][C:21]=3[CH:22]=[CH:23][CH:24]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1cccc2[nH]cnc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc3[nH]cnc23)o1

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 1H-benzoimidazole-4-carboxylic acid instead of o-toluic acid to the title compound (SiO2, dichloromethane:methanol:ammonia=95:5:0)=100:0 to 80:20, 32 mg, 10%) which was obtained as a white solid. MS: m/e=344.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25](Cl)=[N:26]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:26]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)Cc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Cc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of methyl isobutyrylacetate (1.93 g, 13.4 mmol) in tetrahydrofuran (2.7 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (27 mL, 13.5 mmol) was added. A solution of 2-(2,6-dichlorophenyl)-N-hydroxyethanimidoyl chloride (2.60 g, 11.18 mmol) in tetrahydrofuran (8.7 mL) was added and the solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated then partitioned between water and ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0%-30% ethyl acetate in hexane) to provide the title compound (1.10 g, 30%). 1HNMR (DMSO-d6): δ 7.48 (d, J=8 Hz, 2H), 7.34 (t, J=8 Hz, 1H), 4.42 (s, 2H), 3.84 (s, 3H), 3.68 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:19]([OH:21])=[O:20])[C:12]=1C1C=CC=CC=1)[NH:9][CH2:8][CH2:7][CH:6]2[C:22]([OH:24])=[O:23])#N.[OH-:25].[Na+].Cl.[OH2:28]>>[C:3]1([CH:8]2[CH2:7][CH:6]([C:22]([OH:24])=[O:23])[C:5]3[C:10](=[C:11]([C:19]([OH:21])=[O:20])[CH:12]=[C:3]([C:1]([OH:28])=[O:25])[CH:4]=3)[NH:9]2)[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: N#Cc1cc2c(c(C(=O)O)c1-c1ccccc1)NCCC2C(=O)O
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CC(c1ccccc1)N2
Yield: 76.4 %

Procedure:
A solution of the compound obtained in example 17 b) (5.6 g) and sodium hydroxide (5 g) in water (20 ml) was refluxed for 10 hours. After cooling, water (200 ml) was added and the mixture was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The resulting precipitate from the mixture was collected by filtration, washed with water, dried to give the title compound (3.05 g, 76.4%) which was recrystallized from DMF-ethanol to white crystals, mp 300° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([O:17][CH3:18])[CH3:16])[C:9]=1[NH2:10].[Cl:20][CH2:21][C:22](Cl)=[O:23].O>C(Cl)Cl>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([O:17][CH3:18])[CH3:16])[C:9]=1[NH:10][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: O=C(Cl)CCl
Reactant: COC(C)(C)c1cccc(C)c1N
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(C)(C)c1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
216.46 g (2.74 mols) of pyridine was slowly added to a solution containing 467.5 g (2.61 mols) of 2-methyl-6-(1-methyl-1-methoxyethyl)-aniline in 2.74 liters of methylene chloride at room temperature (about 18°-25° C.). 309.62 g (2.74 mols) of chloroacetyl chloride was added dropwise over a 20-minute period. The temperature of the mixture was maintained at about, or less than, 25° C. during this addition. The mixture was then stirred at about 18° C. for about 1 hour and then mixed with two liters of water. The methylene chloride phase was then separated treated with aqueous 5 wt. % hydrochloric acid until slightly acidic and then washed with water and dried over magnesium sulfate. The mixture was then evaporated to dryness affording a brownish solid which was then washed with a 10% isopropanol:90% hexane mixture affording 484 g of the title compound.
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([F:26])[C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)=O)(C)(C)C.[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:30]1([S:27]([C:21]([CH:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=4)[NH:8][C:20]=3[CH2:19]2)([F:26])[C:22]([N:23]([CH3:39])[CH3:24])=[O:25])(=[O:28])=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CI
Reactant: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
680 mg (1.27 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 10 mL of DMF were treated with 83 mg (1.90 mmol, 1.5 eq) of NaH (55% in oil) portionwise within 30 min at 0° C. 217 mg (1.52 mmol, 1.2 eq) of methyliodide were added and the reaction was stirred an additional 30 min, and then poured into water and extracted with EtOAc. The crude material was dissolved in 10 mL of CH2Cl2, and 1 mL of TFA was added at RT. Aqueous Na2CO3 was added until pH=7 was reached, and the organic phases were dried on Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1:1 yielded 420 mg (65%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N,N-dimethyl-acetamide as a white solid, MS: 449 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=O)=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:47][C:48]1[C:56]2[C:55]([NH2:57])=[CH:54][CH:53]=[CH:52][C:51]=2[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][C:55]=2[NH:57][C:19]([C:16]2[N:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:11][C:12]3=[N:18][CH:17]=2)=[O:21])[N:50]([CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([CH3:65])[N:60]=2)[N:49]=1
Reactant: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCOCC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.055 g, 0.186 mmol) was dissolved in dimethylformamide (0.6 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (53 mL, 0.17 mmol), 3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (Example 35, Steps A-D; 0.042 g, 0.167 mmol), and diisopropylethylamine (0.058 mL, 0.334 mmol) were combined in a 1 dram vial. The mixture stirred at ambient temperature overnight. The crude mixture was purified using preparative thin layer chromatography (silica, 20×20 cm, 1 mm) developed in a chamber with 10% Methanol/dichloromethane to give N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxamide (6 mg). MS m/z 526.1 (M+, APCI+).
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH:10]1([O:16][C:2]([NH:1][CH2:4][C:5]([OH:7])=[O:6])=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CN=C=O
Reactant: OC1CCCCC1
Solvent: ClCCl
Product: O=C(O)CNC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
620 mg (4.80 mmol) of ethyl isocyanatoacetate was dissolved in 5 ml of dichloromethane. 10 ml of a solution of 0.56 ml (5.28 mmol) of cyclohexanol in 10 ml of dichloromethane was added to the obtained solution under cooling with ice, and they were stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. 5.8 ml of 1 N aqueous lithium hydroxide solution was added to the concentrate, and the obtained mixture was stirred in a solvent mixture of methanol:water=2:1 at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the concentrate and the resultant aqueous layer was washed with ethyl acetate. 0.1 N aqueous hydrochloric acid solution was added to the aqueous layer to control pH at 2 to 3. After extracting with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=C[C:16]=2[CH2:15][CH:14](CO)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:17]2=[CH:18][CH:19]=[CH:20][C:6]([CH:5]=[O:9])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCC1CCOc2ccccc2C1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cccc2c1CCCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
DMSO (1.85 ml, 26 mmol) was added slowly to a -78° C. solution of oxalyl chloride in methylene chloride (10 ml of 2M, 20 mmol). To this solution was added slowly a solution of 2,3,4,5-tetrahydrobenzoxepin-4-methanol (2.3 g, 13 mmol) in methylene chloride, and the mixture was stirred 30 min at -78° C. Triethyl amine (7.53 ml, 52 mmol) was added slowly to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with methylene chloride (50 ml) and washed with water and then brine. The organic layer was concentrated in vacuo to an oil (2.28 g, 100%).
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[S:17].C(#N)C.C(N(CC)CC)C>C(OCC)(=O)C>[F:14][C:15]([F:20])([F:19])[C:16]1[S:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:18]=1
Reactant: NC(=S)C(F)(F)F
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(C(F)(F)F)nc1C(F)(F)F
Temperature: 34 °C
Reaction time: 8 h

Procedure:
To a 3L 4-neck RBF equipped with a mechanical stirrer, reflux condenser, thermometer and addition funnel was charged 358 g of ethyl chlorotrifluoroacetoacetate (1.64 moles), 2,2,2-trifluorothioacetamide and 1000 mL of acetonitrile. To this mixture was added 331.9 g of triethylamine (2.0 eq, 3.28 moles) dropwise over 2.5 hours. During the addition the temperature was maintained at 30-38° C. and upon completion of the addition the reaction was heated to reflux for 2 hours and stirred overnight at room temperature. The reaction mixture was filtered and the resulting filtrate was concentrated by rotary evaporation to provide an oily solid which was dissolved in 1500 mL of ethyl acetate. This was washed with 2×500 mL of water, 1×500 mL of brine and concentrated by rotary evaporation to yield 356.6 g of ethyl 2,4-bis-trifluoromethyl-5-thiazole carboxylate which was purified by distillation.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-cyanophenylboronic acid (185 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 110 mg, 0.42 mmol, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.22 (s, 2H), 6.93 (s, 1H), 7.14 (s, 1H), 7.54 (dd, J=8.2, 2.3 Hz, 1H), 7.60 (s, 1H), 7.75-7.78 (m, 3H), 8.11 (d, J=8.2 Hz, 2H), 8.62 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 112.9, 118.6, 119.0, 121.0, 127.4, 130.5, 131.5, 132.6, 136.0, 137.3, 142.6, 148.8, 150.4; MS (ESI): m/z=261.03 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH:10]([CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C(CCN1C(=O)C2=CC=CC=C2C1=O)NC(OC(C)(C)C)=O)C=C.[CH3:61][O:62][C:63]1[CH:68]=[CH:67][C:66]([S:69]([Cl:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1>>[O:62]([C:63]1[CH:64]=[CH:65][C:66]([S:69]([Cl:72])(=[O:71])=[O:70])=[CH:67][CH:68]=1)[C:61]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1.[CH2:1]([O:8][C:9](=[O:32])[CH:10]([CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])[NH:11][S:69]([C:66]1[CH:65]=[CH:64][C:63]([O:62][CH3:61])=[CH:68][CH:67]=1)(=[O:71])=[O:70])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(CCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Agent: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Product: COc1ccc(S(=O)(=O)NC(CCN2C(=O)c3ccccc3C2=O)C(=O)OCc2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Yield: 61 %

Procedure:
In a similar manner to the procedures described in Example 1(2)-a and b, reactions were carried out using (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine benzyl ester, the product of Example 19(1), instead of (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine allyl ester, and using 4-methoxybenzenesulfonyl chloride, instead of 4-phenoxybenzenesulfonyl chloride, to afford the desired compound (yield 61%) as a white powder.