Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([C:12](O)=[O:13])=[CH:10][N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:5][C:6]1[C:11]([C:12]([NH2:18])=[O:13])=[CH:10][N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1ncc(C(=O)O)c(NC(C)(C)C)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(NC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
4-(tert-Butylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (2.83 g, 11.73 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluoro-phosphate(V) (6.69 g, 17.59 mmol) were combined in a 250 mL round-bottomed flask followed by the addition of DMF (29 mL). After that ammonia hydrochloride-(3.14 g, 58.6 mmol) and DIEA (10.21 mL, 58.6 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and water (150 mL) was added. The resulting suspension was filtered, washed with water and dried under high vacuum overnight to afford 4-(tert-butylamino)-2-(methylthio)-pyrimidine-5-carboxamide (2.54 g, 10.57 mmol, 90% yield). MS (ESI) m/z 241.2
Reaction SMILES: [Na+].CS([CH2-])=O.[H-].[Na+].[C:8]([N:11]1[CH2:16][CH2:15][C:14]([C:18]#[CH:19])([OH:17])[CH2:13][CH2:12]1)(=[O:10])[CH3:9].F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]>O.CS(C)=O>[C:8]([N:11]1[CH2:16][CH2:15][C:14]([C:18]#[CH:19])([O:17][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:13][CH2:12]1)(=[O:10])[CH3:9]
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.7 %

Procedure:
To a stirred solution of dimsyl sodium, prepared from 16.5 g of sodium hydride (50% in oil, washed three times with hexanes) and 400 ml of dimethylsulfoxide at 17°-25° was added, in aliquots, 57.7 g of 1-acetyl-4-ethynyl-4-piperidinol. Upon completion of the addition, 55.3 g of 2-fluoronitrobenzene was added dropwise at a rate such that the temperature remained below 25°. The mixture was stirred at room temperature for 20 min, poured into cold water, extracted three times with ether, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided an oil, which crystallized on standing. Recrystallization from ethyl acetate/cyclohexane provided 23.6 g (24%) of product, mp 112°-115°.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=[C:15]2[C:14]=1Cl)(=[O:12])[NH2:11].[CH3:28][C@:29]1([NH2:37])[CH2:33][CH2:32][C@@H:31]([NH2:34])[C:30]1([CH3:36])[CH3:35]>CN(C)C=O>[NH2:37][C@@:29]1([CH3:28])[CH2:33][CH2:32][C@@H:31]([NH:34][C:14]2[C:15]3[N:16]([CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=3)[N:17]=[CH:18][C:13]=2[C:10](=[O:12])[NH2:11])[C:30]1([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Reactant: CC1(C)[C@H](N)CC[C@]1(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
N,N-Diisopropylethylamine (7.18 mL, 41.1 mmol) was added to a mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (3.67 g, 13.71 mmol, from Preparation 4), (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (2.93 g, 20.57 mmol, prepared according to conditions described in Tetrahedron Asymmetry 2001, 12, 1579 and Eur. J. Inorg. Chem. 2006, 839) and N,N-dimethylformamide (50 mL). The mixture was stirred in a 90° C. oil bath for 1 h, quenched with saturated sodium bicarbonate (250 mL) and extracted with ethyl acetate (4×200 mL). The combined extracts were dried (MgSO4), filtered, concentrated and pumped under vacuum. The solid residue was treated with ethyl acetate (60 mL) and sonicated for 10 min. Vacuum filtration gave the first batch of the title compound (2.292 g). The filtrate was concentrated to dryness. The solid residue was treated with dichloromethane (5 mL), ethyl acetate (4 mL) and hexanes (16 mL). The mixture was sonicated for 15 min and filtered. The solid was washed with 20% ethyl acetate in hexanes to give second batch of the title compound (2.146 g). The combined amount of the title compound was 4.438 g (87% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 8.19 (1 H, s), 8.00 (1 H, d, J=1.66 Hz), 7.33 (1 H, d, J=1.66 Hz), 4.47 (1 H, t, J=8.18 Hz), 4.35 (2 H, q, J=7.03 Hz), 2.21-2.49 (1 H, m), 1.77-1.93 (2 H, m), 1.63-1.75 (1 H, m), 1.38 (3 H, t, J=7.21 Hz), 1.21 (3 H, s), 1.07 (3 H, s), 0.96 (3 H, s); MS (ES+) m/z: 374.2 (M+H); HPLC retention time: 2.975 min (analytical HPLC Method F).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.N.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1cc2c(C)cccc2n1CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)cccc2n1CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
A mixture of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-4-methyl-1H-indole-2-carboxylate (27.2 g, 78.5 mmol), trifluoroacetic acid (75 ml) and dichloromethane (250 ml) was stirred at 0° C. for 3 hours, slowly poured into cold aqueous ammonia, and then extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, after which the residue was dissolved in pyridine (150 ml) and the resulting solution was cooled to 5° C. p-Toluenesulfonyl chloride (22.4 g, 118 mmol) was added to the cooled solution in small portions and the resulting mixture was stirred at 5° C. for 3 hours and then allowed to stand overnight at room temperature. The reaction mixture was poured into ice water and extracted twice with ethyl acetate, and the extract solution was washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 27.6 g of ethyl 1-[2-(4-methylphenylsulfonyl)aminoethyl]-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].O>C1CCN2C(=NCCC2)CC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Reactant: NCC(=O)O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 150 °C

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) and glycine (4.8 g, 0.06 ml) in DBU (100 ml) is heated at 150° C. under an atmosphere of argon for 40 hours. The still hot reaction mixture is poured into water. After washing the aqueous phase with ethyl acetate the pH is adjusted to 5 by adding citric acid. The resulting precipiate is filtered and recrystallized from dimethylformamide/ethanol to give the product in form of yellow crystals, m.p. 136–138° C. (with decomposition).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[C:30][Si](C)(C)C)=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>O1CCCC1>[CH2:7]([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[CH:30])=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Potassium carbonate (295 mg, 2.136 mmol), 3,4-bis(benzyloxy)-6-((trimethylsilyl)ethynyl)pyridazine (Intermediate 4; 830 mg, 2.14 mmol) and methanol (10 ml) were added to tetrahydrofuran (5 ml) to produce an orange suspension. The mixture was stirred for 1 hour and then partitioned between brine and ethyl acetate. The organic layer was washed with brine and evaporated before the residue was purified by silica chromatography (eluting with 10-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-ethynylpyridazine (530 mg, 1.68 mmol, 78% yield).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([CH:19]=[N:20][OH:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O.[CH2:30]([Br:33])[C:31]#[CH:32].C(N(CC)CC)C>ClCCl>[Br:33][CH2:30][C:31]1[O:21][N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[CH:32]=1
Reactant: COc1cccc2c(C=NO)cn(CC3CCCCC3)c12
Reactant: C#CCBr
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(-c3cc(CBr)on3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carbaldehyde oxime (170 mg, 0.59 mmol) in dichloromethane (5 ml) cooled to 0° C., was added N-chlorosuccinimide (119 mg, 0.89 mmol) and the mixture allowed to warm to room temperature with stirring for 1 h. Propargyl bromide (8 μl, 0.65 mmol) and triethylamine (9 μl, 0.65 mmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography eluting with 60-80% (v/v) dichloromethane in n-heptane to afford 3-(5-bromomethyl-isoxazol-3-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (150 mg, 0.37 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(OCC)C>[Cl:1][CH2:2][C:3]([O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)OC1CCCCC1
Yield: 98 %

Procedure:
Chloroacetyl chloride (40 mL, 500 mmol) was added dropwise to a solution of cyclohexanol (52 mL, 500 mmol) and triethylamine (77 mL, 550 mmol) in diethyl ether cooled to below 5° C. Upon completion of the addition, the mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed twice with 1M HCl and twice with brine, and was then dried over MgSO4, filtered and evaporated to afford cyclohexyl chloroacetate (86.5 g, 490 mmol, 98%) as a colorless liquid, bp 100° C./5 mm. The chloroacetate (79.5 g, 450 mmol) was added dropwise to a suspension of sodium azide (36.6 g, 563 mmol) in dimethylformamide (60 mL) maintained below 20° C. The mixture was stirred at room temperature overnight, and then was poured into water (200 mL), and the solution was extracted with ether (4×200 mL). The combined organic extracts were washed with brine, then dried, filtered and evaporated to yield cyclohexyl azidoacetate (78.4 g, 428 mmol, 95%) as a colorless liquid, b.p. 85°-90° C. (0.1 mm). Catalytic reduction of the azide with hydrogen over 10% palladium on carbon in ethanol afforded cyclohexyl glycinate, treatment of which with dry HCl afforded glycine cyclohexyl ester HCl, m.p. 144°-145° C., in quantitative yield after crystallization from diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([C:18]([N:20]2[CH2:24][CH2:23][C@@H:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:21]2)=[O:19])[CH2:17][CH2:16]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:29][NH:28][C:26](=[O:27])[CH2:25][C@@H:22]2[CH2:23][CH2:24][N:20]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:21]2)=[O:10])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C=Nc1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a round-bottom flask was added 4-bromo-1-isocyanato-2-(trifluoromethyl)benzene (0.4 mL, 2.55 mmol) and dichloromethane (10 mL) under nitrogen. The mixture was cooled to −78° C. and a solution of 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (520 mg, 2.461 mmol) in dichloromethane (15 mL) was then added to the cooled solution and immediately allowed to warm to room temperature. After 1 h, analysis by LCMS indicated desired product formation. The resulting precipitate was collected and dried under vacuum filtration to yield the title product as a white solid (130 mg, 88%). MS(ES)+ m/e 476.9, 478.9 M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[S:40][C:41]([C:44]([NH:46][CH:47]2[CH2:49][CH2:48]2)=[O:45])=[CH:42][N:43]=1.ClC1SC(C(NC2CC2)=O)=CN=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:47]1([NH:46][C:44]([C:41]2[S:40][C:39]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:7]5[O:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=5)[CH:11]=4)[N:15]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:20])=[O:21])[CH:14]=3)=[N:43][CH:42]=2)=[O:45])[CH2:48][CH2:49]1
Reactant: O=C(NC1CC1)c1cnc(Br)s1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(NC1CC1)c1cnc(Cl)s1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(C(=O)NC4CC4)s3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 130 °C
Yield: 75 %

Procedure:
A mixture of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (150 mg, 0.287 mmol), 78 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide, Pd2(dba)3 (Strem Chemicals, 8 mg, 8.6 μmol), Xphos (Stem Chemicals, cat #15-1152, 9 mg, 17 μmol), potassium phosphate (183 mg, 0.861 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 25 min. LCMS indicated the presence of desired product (M+1=563.0), as well as a significant amount of the starting N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine. To the reaction mixture was added Pd(PPh3)4 (Strem Chemicals, cat #46-2150, 10 mg) and 50 mg of the 1:1 mixture of 2-bromo-N-cyclopropylthiazole-5-carboxamide and 2-chloro-N-cyclopropylthiazole-5-carboxamide. It was heated again at 130° C. for 15 min in an Initiator microwave reactor. The reaction mixture was treated with water (5 mL) and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica gel flash chromatography using a gradient of 20-100% EtOAc in hexanes to give N-cyclopropyl-2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)thiazole-5-carb oxamide (60 mg, in 75% purity) as a brown amorphous solid. MS (ESI, pos. ion) m/z: 563.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][C:11]3([CH3:21])[CH3:20])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1.[H-].[Na+].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][Cl:33])[CH2:27][CH2:26]1>CN(C)C=O>[ClH:33].[CH3:1][CH:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][C:11]3([CH3:21])[CH3:20])=[N:6][N:5]([CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)[C:4](=[O:22])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(=O)N(CCN2CCOCC2)N=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of 3 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one in 30 ml of dimethylformamide was added 0.9 g of 50% sodium hydride. After stirring for about 30 minutes, 1.7 g of 2-morpholinoethyl chloride was added and the mixture was stirred at about 50° C. for one hour. The reaction mixture was poured into 200 ml of ice-cold water and extracted with 150 ml of chloroform. The extract was dried over potassium carbonate and concentrated under reduced pressure. To the residue was added alcoholic hydrogen chloride and the precipitated crystals were filtered off. Recrystallization from isopropanol gave 2.5 g of 6-[5-methyl-2-(2-morpholinoethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one hydrochloride, melting at 243°-246° C.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[C:13]([O:20][CH3:21])[CH:12]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: N#Cc1cccnc1Cl
Product: COc1cc(F)ccc1-c1ncccc1C#N
Yield: 85 %

Procedure:
Prepared in 85% yield from 2-chloronicotinonitrile and 4-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 6.75-6.84 (m, 2H), 7.37 (dd, J=8.0, 4.9 Hz, 1H), 7.44 (dd, J=8.5, 6.8 Hz, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H), 8.86 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[OH:39]>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH:38]([OH:39])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:18])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: NCC(O)c1ccccc1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and (1RS)-2-amino-1-phenylethanol, the title compound was obtained in 83% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:19]=[O:20])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCc3ccccc32)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Into a 1,000 mλ reaction flask equipped with a thermometer, a stirrer, a condenser and a dropping funnel, 209 g (1.0 mol) of 1-benzylindoline and 365.5 g (5.0 mols) of N,N-dimethylformamide (DMF) were charged, and the temperature was raised to a liquid temperature of from 30 to 40° C. Then, while stirring at the same temperature, 161.0 g (1.05 mols) of phosphorus oxychloride was dropwise added thereto over a period of about two hours from the dropping funnel. After completion of the dropwise addition, stirring was continued for three hours at from 80 to 100° C. After completion of the reaction, the reaction solution was cooled to room temperature and put into 1 kg of ice water. At a temperature of from 30 to 40° C., a 24% sodium hydroxide aqueous solution was dropwise added thereto to bring the liquid alkaline, whereby the precipitated solid was collected by filtration, washed with water and dried to obtain 230.2 g (yield: 97%) of 1-benzyl-5-formylindoline as a slightly yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[CH:20]=[N:21][O:22][C:23]=1[CH3:24])=O)=[N+]=[N-].C[N:26](C)[CH:27]=[O:28]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:27]([NH:26][C:19]2[CH:20]=[N:21][O:22][C:23]=2[CH3:24])=[O:28])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Cc1oncc1C(=O)N=[N+]=[N-]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CN(C)C=O
Product: Cc1oncc1NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 23 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (238 mg, 1.07 mmol) and the crude material of 4-(azidocarbonyl)-5-methylisooxazole in 5 mL of N,N-dimethyl-formamide was stirred for 18 hours at room temperature. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (86 mg, 23%). LC-MS (m/z) 347.0 (M+).
Reaction SMILES: C1N(P(N2CC2)(N[C:7]([C:9]2[C:14](I)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=O)C1.[C:19]([O:24][CH2:25]CCC)(=[O:23])[C:20]([CH3:22])=[CH2:21]>O>[CH2:19]=[CH:7][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1.[C:19]([O:24][CH3:25])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)OCCCC
Reactant: O=C(NP(=O)(N1CC1)N1CC1)c1ccccc1I
Solvent: O
Product: C=C(C)C(=O)OC
Product: C=Cc1ccccc1
Reaction time: 0.5 h

Procedure:
50 g of deionized water and 211 g of Aerosol A-103 (34% solid content) are mixed in a 3 liter, four-neck resin kettle and mechanically stirred for 30 minutes under the atmosphere of nitrogen gases. The monomer mixture is obtained by the addition of 585 g of styrene 225 g of butyl methacrylate, and 90 g of methyl methacrylate in a 2 liter Erlermeyer flask with magnetic stirring. 168 g this monomer mixture is then slowly added into the 3 liter resin kettle within a one hour period through a 250 ml separatory funnel with a drop-regulator (FIGS. 1, 2 and 3). After the addition of 20 ml of 20% aqueous ammonium persulfate (containing 8% aerosol A-103) and 20 ml of 20% sodium metabisulfite(containing 8% aerosol A-103) the temperature is raised to 70° C. The rest of the monomer mixture, 732 g, is then slowly added to the reaction emulsion within 5 hours period while bubbling of nitrogen gases and mechanical stirring (400 rpm) are continuing. The polymerization is completed after heating the reaction mixture for 1.5 hours at 75° C. The final product is slowly cooled to room temperature. An emulsion polymer is obtained with a weight of 1200 g. This emulsion polymer have solid content around 74%.