Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:38]=[N:37][C:26]4[NH:27][C:28]5[CH:33]=[N:32][C:31]([C:34]([OH:36])=O)=[CH:30][C:29]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.C1CN([P+]([O:55]N2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(CN)O.S(=O)(=O)(O)O>CN(C=O)C>[OH:55][CH2:1][CH2:2][NH:3][C:34]([C:31]1[N:32]=[CH:33][C:28]2[NH:27][C:26]3[N:37]=[CH:38][C:23]([C:20]4[CH:19]=[CH:18][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]5)=[CH:22][CH:21]=4)=[CH:24][C:25]=3[C:29]=2[CH:30]=1)=[O:36]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)O)cc5c4c3)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: NCCO
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)NCCO)cc5c4c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
DIPEA (13.5 μL, 77.4 μmol) was added to a solution of 3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (20.0 mg, 51.6 μmol), PyBOP (28.2 mg, 54.2 μmol) and HOBt (8.4 mg, 62 μmol) in DMF (0.6 mL). After 10 min at ambient temperature, ethanolamine (16 μL, 0.26 mmol) was added to the reaction mixture. After 30 min the resultant mixture was acidified with 10% aqueous sulfuric acid and concentrated in vacuo. The resultant residue was dissolved in DMF, water and 10% aqueous sulfuric acid and purified by preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.49 (s, 1H), 9.71 (br.s, 1H), 9.14 (d, J=2.1 Hz, 1H), 8.90 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.66 (t, J=5.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 3.97 (d, J=13.4 Hz, 2H), 3.57 (m, 4H), 3.45 (m, 2H), 3.20 (m, 2H), 3.04 (m, 2H), 2.89 (s. 3H), LCMS (Method D): RT=6.31 min, M+H+=431.
Reaction SMILES: [CH:1]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]([O:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:28])=[CH:23][CH:24]=2)[C:19]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[CH:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[C:59]1([CH3:69])[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[S:65]([NH2:68])(=[O:67])=[O:66]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]([NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([NH:26][C:27]([O:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])=[CH:23][CH:24]=2)[C:19]([CH2:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([NH:68][S:65]([C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=3[CH3:69])(=[O:67])=[O:66])=[O:41])=[CH:38][C:37]=2[O:45][CH3:46])=[CH:18]1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C(=O)NC(c2ccccc2)c2ccccc2)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
To a solution of 4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.50 grams, 0.81 mmol), 4-dimethylaminopyridine (0.015 grams, 1.21 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (0.23 g, 1.21 mmol) in methylene chloride (30 mL) was added o-tolylsulfonamide (0.14 g, 0.81 mmol). The resulting solution was stirred for 12 hours at room temperature. The solution was diluted with methylene chloride and washed with 1 M hydrochloric acid (aq). The organics were dried over magnesium sulfate and concentrated. Chromatography on silica gel (2% methanol/methylene chloride), followed by recrystallization from wet ether gave the titled compound (0.455 grams, 73% yield). m.p.=253-254° C. Anal. calcd. for C44H42N4O7S: C, 68.55; H, 5.49; N, 7.27. Found: C, 69.21; H, 5.54; N, 7.14. HRMS calcd. for C44H42N4O7S: 770.2774. Found 770.2736.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2C(=O)[CH:17](C(C)C)[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[C:7]1([CH2:13][N:14]2[C:29](=[O:30])[CH:28]([CH2:27][CH2:31][CH3:1])[N:16]([CH3:17])[S:15]2(=[O:24])=[O:23])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: CC(C)C1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of potassium t-butoxide (3.53 g, 29 mmol) in THF was added a solution of 2-phenylmethyl-4-isopropyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.7 g, 29 mmol) in THF at 0° C and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (20.38 g, 0. 143 mol) and the resulting mixture was allowed to stir at room temperature for 2.5 hours. The resulting mixture was quenched with brine, extracted with ether, and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 7.1 g (88%) of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =isopropyl, R3 =methyl) as a solid, m.p. 52.5°-54° C.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1.[ClH:33]>C(#N)C.[Cu](Cl)Cl>[Cl:33][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([C:24]#[N:25])=[C:12]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:11]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under argon, 24.5 g (182 mmol) of anhydrous copper(II) chloride are suspended in 180 ml of acetonitrile, and 21.4 g (182 mmol) of isopentyl nitrite are then added dropwise. After 20 min of stirring at room temperature, 10 g (30.5 mmol) of 2-amino-4-phenyl-6-(phenylsulfanyl)-3,5-pyridinedicarbonitrile [Kambe et al., Synthesis, 531-533 (1981)] are added. The mixture is stirred at room temperature over the weekend. For work-up, 150 ml of 1 N hydrochloric acid are added to the mixture, the mixture is extracted 4× with dichloromethane and the organic phase is washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a little ethyl acetate and allowed to stand in a fridge for 1 hour. The crystals are filtered off with suction and washed with a little cold ethyl acetate and diethyl ether.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4](=[CH2:7])[C:5]#[CH:6].[CH2:8]([C:12]([CH3:14])=O)[CH:9]([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[CH3:10][CH:9]([CH2:8][C:12]([CH3:14])([OH:1])[C:6]#[C:5][C:4]([CH3:7])=[CH2:3])[CH3:11]
Reactant: [OH-]
Reactant: CC(=O)CC(C)C
Reactant: C#CC(=C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)C#CC(C)(O)CC(C)C
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
400 ml of anhydrous toluene and 200 g of powdered potassium hydroxide are added to a 2 liter round flask which is provided with a stirrer, condenser, thermometer and dropping funnel. The mixture is cooled to -20° C. and there are now added thereto at a temperature between -20° C. and -10° C. 66g (1 mol) of 3-methyl-3-buten-1-yne [A. F. Thompson jun. N. A. Milas, Ida Rovno, J. Am. Chem. Soc. 63, (1941), 752-755]. The mixture is held at a temperature of -10° C. for 1.5 hours while stirring and there are slowly added thereto at 0° C. 110 g (1.1 mol) of methyl isobutyl ketone. The mixture is now stirred at 0° C. for 1 hour and then the temperature is allowed to rise to 20° C. within 2 hours with further stirring. The mixture is added to ice, extracted with 500 ml of toluene and washed with brine until neutral. The solvent is then evaporated. There are obtained 183 g of crude product, distillation of which yields 129.5 g (78.4%) of 2,4,7-trimethyl-7-octen-5-yn-4-ol of boiling point 76°-77° C./5 mmHg; nD20 =1.4690; d420 =0.8620.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH2:1]=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Potassium tert-butoxide (0.62 g, 5.5 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.98 g, 5.5 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for one hour. A solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in tetrahydrofuran (5 mL) was then added and the resulting mixture was stirred at 35° C. for two hours. The mixture was cooled, diluted with hexane (100 mL), filtered, and the filtrate was washed with water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to give tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (0.45 g, 91% yield). GC-MS (EI) for C13H21NO2: 223 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)(Cl)Cl>[C:35]([O:27][CH2:26][CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Yield: 86.3 %

Procedure:
To a solution of 5.2 g of the compound of Example 43 in 30 ml of chloroform is added 2.1 g of triethylamine, and the mixture is cooled and then stirred. To the reaction mixture is added dropwise 1.7 g of acetyl chloride below 0° C. over 5 minutes. After completion of the addition, the mixture is stirred at room temperature for 3 hours, and the reaction solution is washed with water, dried and concentrated. The residue is recrystallized from isopropyl alcohol to give 5 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 115°-116° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13].C(N(CC)CC)C>C(C(C)=O)C>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[S:7][C:6]=3[CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CCc1cccc(N=C=O)c1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cccc(NC(=O)Oc2ccc3oc(=O)sc3c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (15.0 grams) was mixed with 3-ethylphenyl isocyanate (13.1 grams) in 180 milliliters of methyl ethyl ketone in the presence of 0.90 gram of triethylamine. This solution was heated at reflux temperature with stirring for 3 hours and 15 minutes. The solvent was then removed by evaporation in vacuo and the residual, viscous oil was dissolved in a hot mixture of ethyl acetate and methylcyclohexane. Upon slowly cooling to room temperature, the solution gave the purified 5-[(3-ethylphenyl)carbamoyloxy]-1,3-benzoxathiol-2-one as a white crystalline solid with a melting point of 96°-97° C. Elemental analysis calculated for C16H13NO4S (percent): carbon--60.94; hydrogen--4.15; nitrogen--4.44. Found: carbon--61.2; hydrogen--4.26; nitrogen--4.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH:27]1([NH:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:15][N:14]1[C:16]1[N:33]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:34]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: NNC1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCCCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with cyclohexylhydrazine hydrochloride (CAS Reg. No. 24214-73-1) to give the title compound as orange oil. MS (ESI): m/z=466.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Mg].[Br-].CON(C)[C:16]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)=[O:17]>CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:16]([C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][CH:19]=1)=[O:17]
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1F)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4-Difluorobenzyl bromide (23.7 ml, 0.114 mol) was added dropwise to a stirred mixture of magnesium turnings (8.1 g, 0.183 mol) in dry ether (300 ml) under nitrogen. The mixture was warmed initially until reaction started, and thereafter the bromide was added at such a rate as to maintain a gentle reflux. After 1 hour, the resulting solution of the Grignard reagent was added dropwise at −78° C. to a solution of O,N-dimethyl-4-iodobenzenehydroxamic acid [see step (a)] (45.7 g, 0.157 mol) in dry ether (300 ml), and the mixture was allowed to warm slowly to room temperature overnight. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate, and the organic solution was separated, dried (MgSO4) and concentrated under reduced pressure, to give the title compound as a white solid, 38.71 g (69%), which was characterised by 1H-N.M.R. spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[O:30])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c(=O)[nH]c23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Yield: 38 %

Procedure:
Method F2 was used with 8-(4-aminophenoxy)pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione and 4-chloro-3-trifluoromethylphenyl isocyanate to obtain the tithe compound (yield 38%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]#[C:11][CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>C(OCC)(=O)C>[CH3:21][S:22]([O:13][CH2:12][C:11]#[C:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC#CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC#CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-1-ol (701.4 mg) was dissolved in ethyl acetate (15 mL), and the solution was cooled to 0° C. Triethylamine (1.1 mL) and methanesulfonyl chloride (0.3 mL) were added, and the mixture was stirred at 0° C. for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→50:50) to give the title compound (469.7 mg) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([OH:36])[CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:12][CH2:13][C@@H:14]1[O:18][C:17]([C:19]2[NH:23][C:22]([C:24]3[CH:25]=[C:26]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:29]=3)[O:36][C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=3)=[CH:21][CH:20]=2)=[N:16][CH2:15]1
Reactant: CNC(=O)c1ccc(F)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(-c3ccc(C4=NC[C@H](CO)O4)[nH]3)c2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
5-Fluoro-N-methylpyridine-2-carboxamide (150 mg, 0.97 mmol) synthesized in Example (123a) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (438 mg, 1.27 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (3 mL), and potassium carbonate (269 mg, 1.95 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was carried out twice with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (281 mg, yield 60%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OC[CH:22]([N:26]=[N+:27]=[N-:28])[CH2:23][CH2:24][CH3:25])(=O)=O.N([CH2:32][CH2:33]N1C=CC=C(OC)C1=O)=[N+]=[N-]>>[N:26]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:32][CH2:33][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]1=[O:15])=[N+:27]=[N-:28]
Reactant: COc1cccn(CCN=[N+]=[N-])c1=O
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: CCCC(COS(C)(=O)=O)N=[N+]=[N-]
Product: [N-]=[N+]=NCCCCCCn1cccc(OCc2ccccc2)c1=O
Yield: 60 %

Procedure:
Reaction of 3-benzyloxypyridine-2-one (0.50 g, 2.49 mmol) and 156d (0.66 g, 2.98 mmol) within 16 h as described for synthesis of 157a gave compound 157e (0.48 g, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (m, 5H), 6.65 (dd, J=7.4, 1.8 Hz, 1H), 6.45 (dd, J=7.4, 1.8 Hz, 1H), 5.81 (t, J=7.1 Hz, 1H), 4.92 (s, 2H), 3.76 (t, J=6.8 Hz, 2H), 3.05 (t, J=6.8 Hz, 2H), 1.58 (m, 2H), 1.40 (m, 2H), 1.90 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 157.55, 148.25, 135.95, 128.60, 128.10, 126.95, 126.50, 115.05, 104.90, 70.50, 51.05, 49.20, 28.65, 28.50, 26.20, 25.80. HRMS (FAB) calcd for C18H23N4O2 [M+H]+ 327.1821. found 327.1848.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH:69]([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72]>O1CCCC1.O>[CH2:71]([O:70][CH:69]([O:73][CH2:74][CH3:75])[CH2:68][CH2:67][NH:66][C:15]([C:13]1[S:14][C:7]2[C:8](=[N:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:18]=[CH:19][C:20]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=3[F:32])=[O:23])=[C:2]([F:1])[CH:3]=2)[CH:12]=1)=[O:17])[CH3:72]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Temperature: 60 °C

Procedure:
To a stirred suspension of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (1.0 g, 2.2 mmol) in 20 ml of anhydrous tetrahydrofuran were added HATU (1.0 g, 2.6 mmol) and N,N-diisopropylethylamine (620 mg, 4.8 mmol). The mixture was heated at 60° C. for 20 minutes, followed by addition of 1-amino-3,3-diethoxypropane (388 mg, 2.6 mmol). The mixture was heated at 60° C. for another 30 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as off-white solid. Yield: 1.23 g, 95%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.OS(O)(=O)=O.C(Cl)Cl.CO.[CH3:19][CH2:20]O>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[N:2]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc[nH]n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A 100 mL Schlenk tube was dried under vacuum, filled with nitrogen and charged with 0.5 g (4.461 mmol, 1.0 eq) 1H-pyrazol-3-carboxylic acid which was dissolved in 20 mL EtOH. After adding 1.31 g (0.72 mL, 13.382 mmol, 3.0 eq) conc. H2SO4 the colorless reaction mixture was heated to reflux (100° C.) and stirred at this temperature for 4 h. TLC analysis (DCM/MeOH 95:5) indicated full conversion of the starting material. After cooling to rt the mixture was transferred to a flask to remove the solvent at a rotary evaporator. The colorless residue was diluted in 20 mL water and neutralized with 17 mL saturated aqueous NaHCO3 solution. Thereby a white solid precipitated. The aqueous layer was extracted with EtOAc (4×50 mL), dried over MgSO4 and the solvent was evaporated under reduced pressure to yield the pure title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N:15]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]2)=[CH:9][CH:8]=1)=O.[N:22]1([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH2:37])=[NH:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CCO>[OH:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:10]2[C:11]([C:13]#[N:14])=[N:12][C:7]([C:5]3[CH:4]=[CH:3][N:37]=[C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:33][CH:32]=4)[N:36]=3)=[CH:8][CH:9]=2)[CH2:16]1
Reactant: CN(C)/C=C/C(=O)c1ccc(N2CC[C@H](O)C2)c(C#N)n1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Solvent: CCO
Product: N#Cc1nc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)ccc1N1CC[C@H](O)C1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Compound 66 (150 mg, 0.524 mmol) and N-(4-morpholin-4-yl-phenyl)-guanidine were dissolved in EtOH (4 mL). The mixture was then stirred at 180° C. in the microwave for 30 minutes. The solvent was evaporated in vacuo and the residue diluted with MeOH (50 mL). The solution was heated to 60° C. on a rotary evaporator with swirling. The solution was cooled to rt and the solvent carefully decanted. The process was repeated twice more. The residual solvent was then evaporated in vacuo. The title compound was afforded as a yellow solid (110 mg, 47%); LCMS, Rt=2.58 min (MeOH-FA method), m/z 444 (MH+).