Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:11])[CH2:9][CH3:10])=[C:4]([F:12])[C:3]=1[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14].[N:21]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH:24]=[C:23]([C:26](OCC)=[O:27])[CH2:22]1.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[C:34]([O:33][C:31]([N:21]1[CH2:25][CH:24]=[C:23]([C:26](=[O:27])[NH:11][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[C:4]=2[F:12])[CH2:9][CH3:10])[CH2:22]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC[C@H](N)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)C1=CCN(C(=O)OC(C)(C)C)C1)c1ccc(Cl)c(C(=O)c2cccnc2)c1F
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To (1S)-1-{4-chloro-2-fluoro-3-[(pyridin-3-yl)carbonyl]phenyl}propan-1-amine (0.1 g, 0.3 mmol) (Example 26) in DCM was added 1-tert-butyl 3-ethyl 1H-pyrrole-1,3(2H,5H)-dicarboxylate (0.065, 0.3 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.07 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (0.049 g, 0.36 mmol) and triethylamine (0.085 ml, 0.6 mmol), then stirred at ambient for 18 hours. The reaction was diluted with DCM washed with 5% citric acid, sat. sodium bicarbonate then brine. The organic extract was dried (Na2SO4), filtered and concentrated to give 3-{(S)-1-[4-Chloro-2-fluoro-3-(pyridine-3-carbonyl)-phenyl]-propylcarbamoyl}-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (0.125 g). MS: [M+H]+ 488.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([CH:22]=1)[CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:10][CH:9]=1.[Li]CCCC.[Si:29]([O:36][C@H:37]1[C@H:44]2[C@H:40]([O:41][C:42]([CH3:46])([CH3:45])[O:43]2)[O:39][C@H:38]1[CH:47]=[O:48])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1>[Si:29]([O:36][C@H:37]1[C@H:44]2[C@H:40]([O:41][C:42]([CH3:46])([CH3:45])[O:43]2)[O:39][C@H:38]1[CH:47]([C:2]1[CH:3]=[CH:4][C:5]([Cl:23])=[C:6]([CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:10][CH:9]=2)[CH:22]=1)[OH:48])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31]
Reactant: CC1(C)O[C@@H]2O[C@@H](C=O)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2O[C@@H](C(O)c3ccc(Cl)c(Cc4ccc(O[Si](C)(C)C(C)(C)C)cc4)c3)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A solution of (4-(5-bromo-2-chlorobenzyl)phenoxy)(tert-butyl)dimethylsilane (14.2 g, 34.57 mmol, prepared following the procedure given in US20070049537) in dry THF (90 mL) was cooled to −78° C. and nBuLi (30.7 mL, 46.05 mmol, 1.5 M solution in hexane) was added drop wise while stirring and stirring was continued for further 30 min. A solution of (3aS,5R,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carbaldehyde (7.0 g, 23.05 mmol, prepared according to the procedure given in NUCLEOSIDE, NUCLOETIDES & NUCLEIC ACIDS, 20(4-7), 649-652 (2001)) in dry THF (13 mL) was added dropwise to the reaction mixture and stirred at the same temperature for 2 h. Reaction temperature was raised slowly to 0° C. and then stirred at r.t. for 16 h. After completion of reaction, as confirmed by TLC, reaction mixture was quenched by the addition of saturated NH4Cl solution and extracted with ethyl acetate (3×300 mL). The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.2:9.8 Acetone:Pet. Ether) to afford the title compound (3.66 g, 25%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:6]([CH:8]([CH:10]([C:20]([NH2:22])=[O:21])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH3:9])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(N2CCCCC2)c(C(C)C(C(N)=O)c2ccc(C(=O)O)cc2)c1

Procedure:
An amount of 0.10 gm (0.262 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 1 ml of acetic anhydride was stirred for six hours at 20° C., evaporated in vacuo, and distilled off several times with toluene, and the evaporation residue was recrystallized from ether.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.O.[NH2:19][NH2:20]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:19][NH2:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: NN
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc(Cl)ccc1N)c1ccccc1F

Procedure:
In the manner given in Preparation 1, 2-amino-5-chloro-2'-fluorobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-5-chloro-2'-fluorobenzophenone hydrazone.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:15])=[N:9][C:10]3[N:11]([N:12]=[CH:13][CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[NH2:21][C:2]1[C:7]2[C:8]([CH3:15])=[N:9][C:10]3[N:11]([N:12]=[CH:13][CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cnc2c(c(C)nc3ccnn32)c1Cl
Reactant: N
Product: CCOC(=O)c1cnc2c(c(C)nc3ccnn32)c1N

Procedure:
By treating the product of Example 10 with ammonia according to the procedure of Example 5, 6-amino-5-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester is obtained. Treatment of this product with ethanolic hydrochloric acid yields the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[I:17][C:18]1[CH:19]=[C:20]([CH2:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:25][CH2:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([I:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Reactant: NCc1cccc(I)c1
Solvent: CCCCO
Product: Clc1nc(NCc2cccc(I)c2)c2ncn(C3CCOC3)c2n1
Yield: 53188.9 %

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 133 mg of the product obtained in Stage 1 of Example 2 and 2 ml of butanol and using 0.2 mg of 3-iodo-benzenemethanamine (1.1 eq) in place of the benzylamine. In this way 208 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[F-].[K+].Br[C:13]([CH3:24])([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[Br:9][C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:19](=[O:20])[C:13]([CH3:24])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:8][C:7]=2[CH:6]=1
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: Nc1ncc(Br)cc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Oc2cc(Br)cnc2NC1=O
Temperature: 60 °C
Yield: 60 %

Procedure:
To an ice-cold solution of 2-amino-5-bromopyridin-3-ol (1 g, 5.29 mmol) in DMF (10 mL) was added KF (0.77 g, 13.23 mmol) followed by addition of diethyl 2-bromo-2-methylmalonate (1 mL, 5.29 mmol) and the mixture heated up to 60° C. for 4 h. After completion (by TLC), the reaction was cooled, quenched with water and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the desired product as an off-white solid (1 g, 60%).
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.[CH:48]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49]1.C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:31]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:53][CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)=[NH:47])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Reactant: NC1CCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NC2CCCC2)c1
Reaction time: 72 h
Yield: 77 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a solution of cyclopentylamine (255 mg., 3.0 mmoles), glacial acetic acid (0.3 ml., 5.3 mmoles) and chloroform (10 ml.). The mixture was held for 72 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (3 × 50 ml.), washed with saturated aqueous sodium chloride solution (3 × 50 ml.), dried (Na2SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5 ml.) and then evaporated in vacuo to an oil. The oil was crystallized from warm 1,2-dimethoxyethane [850 mg., 77% yield, Rf 0.30 (4:1, benzene:ethanol on silicic acid), m.p.-forms a gel at 78° C⟧
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:7][C@H:6]([OH:19])[C@@H:5]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:4]1.N1C=CN=C1.[CH:33]([Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])Cl)([CH3:35])[CH3:34]>CN(C)C=O.Cl>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:5]2[CH2:4][C@@H:3]([CH2:2][O:1][Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34])[N:8]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=3)(=[O:10])=[O:11])[CH2:7][C@@H:6]2[OH:19])=[CH:25][CH:24]=1
Reactant: COc1ccc([C@H]2C[C@@H](CO)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2O)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 19.3 g of (3R,4R,6S)-6-hydroxymethyl-4-(4-methoxy-phenyl)-1-(toluene-4-sulfonyl)-piperidin-3-ol in 400 ml of N,N-dimethylformamide is added 10.9 g of imidazole and 6.79 g of triisopropylchlorosilane at room temperature. The reaction mixture is stirred overnight, diluted with 1N hydrochloric acid and extracted with tert-butyl methyl ether. The organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by flash chromatography (SiO2 60 F) to afford the title compound as a light yellow oil. Rf=0.60 (EtOAc-heptane 1:1); Rt=6.39.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].C(CN)O.Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]1[NH:10][C:11](=[O:12])[NH:13][C:14]1=[O:15]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Solvent: NCCO
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2Cl)N1
Reaction time: 4.25 h

Procedure:
A mixture of o-chlorobenzaldehyde (2.50 g.) and hydantoin (1.78 g., 1 molar ratio) was treated with water (15 ml) and heated to 70°. Monoethanolamine (1.63 g., 1.5 molar ratio) was added and the mixture was stirred magnetically at 90°-92° (bath temperature) for 4.25 hours. The mixture was cooled in an ice-bath, acidified with concentrated HCl, refrigerated overnight, filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a pinkish solid (2.63 g.), m.p. 266°-270° decomp.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.O.[NH2:23][NH2:24]>O1CCOCC1>[NH:23]([C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1)[NH2:24]
Reactant: NN
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1nnc(NN)nc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4] triazine-6-carbonitrile was reacted with hydrazine hydrate in dioxane at 140° C. during 3 hours to give 3-hydrazino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a yellow amorphous powder; MS: 282 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[C:5]([CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=O)[CH:4]=1>P(=O)(O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][CH:12]=1)[C:7](=[O:8])[N:9]([CH3:10])[CH:14]=[C:13]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNC(=O)c1ccc(OC)cc1C(C=O)c1ccccc1
Agent: O=P(O)(O)O
Product: COc1ccc2c(=O)n(C)cc(-c3ccccc3)c2c1

Procedure:
4-methoxy-N-methyl-2-(2-oxo-1-phenylethyl)benzamide (100 mg) was dissolved in 2 mL of phosphoric acid with gentle heating. After a solution was obtained, the reaction was partitioned between water and EtOAc. The organic solution was dried (Na2SO4) and concentrated. Flash chromatography (25% EtOAc in CH2Cl2) provided the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15](OC)=[O:16])[CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:14]=[C:6]([CH:5]=[C:4]([CH2:15][OH:16])[CH:3]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl methyl 5-bromoisophthalate (3.63 g, 11.5 mmol) in tetrahydrofuran (90 mL) at 0° C. was added portionwise sodium borohydride (1.53 g, 40.3 mmol). The mixture was stirred at 0° C. After 30 min, methanol (4.2 mL, 92.0 mmol) was added and the mixture was heated to 40° C. After 6 h, the mixture was cooled to ambient temperature and the mixture was quenched with methanol and concentrated. Ethyl acetate was added and the mixture was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (2.7 g).
Reaction SMILES: [C:1]1([C:7]2(CC(O)=O)[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C1C=CC=CC=1>[CH2:9]([O:8][C:7](=[O:11])[CH2:1][CH2:2][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[O:8]1)[CH3:10]
Reactant: O=C(O)CC1(c2ccccc2)Oc2ccc(Cl)cc2O1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CCC1(c2ccccc2)Oc2ccc(Cl)cc2O1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
11.7 g. of (2-phenyl-5-chloro-1,3-benzodioxol-2-yl)-acetic acid mixed with 50 cc. of anhydrous benzene are refluxed with 10 cc. of SOCl2 for 3 hours. The solvent and the excess of SOCl2 are removed under vacuum. The residual oil mixed with 150 cc. of anhydrous ether is added in drops to an ether solution of diazomethane, which is ice cooled to maintain the temperature under 2°-3°C. After 24 h, the ether is removed under vacuum and the residue is mixed with 100 cc. of ethanol. The mixture is heated at 50°C., and 2 g. of Ag2O are added. After 2 hours, the product is treated with animal charcoal, filtered and dried. It is then fractionated and the desired product boils at 200°-207°C./0.4 mm.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:21]([C@H:23]3[CH2:27][N:26]([C@@H](C4C=CC(OC)=CC=4)C)[C:25](=[O:38])[CH2:24]3)[CH3:22])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:21]([C@H:23]3[CH2:27][NH:26][C:25](=[O:38])[CH2:24]3)[CH3:22])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4nc(C)cc34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc2c(O[C@H](C)[C@H]3CNC(=O)C3)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (5 mg) in TFA (2 mL) was heated at 60° C. for overnight, cooled to rt. and then removed TFA under vaco., the residue was diluted with ethyl acetate, and washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 3 mg of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.60.
Reaction SMILES: [C:1]([C:3]1[C:4](OCC(N)=O)=[N:5][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].C[N:26](C)C=O>O.C(OCC)(=O)C>[NH2:26][C:4]1[N:5]=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-c2ccco2)nc1OCC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2ccco2)nc1N
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A suspension of 2-[[3-cyano-6-(2-furyl)-2-pyridyl]oxy]acetamide (8.0 g, 32.9 mmol) and potassium carbonate (9.1 g, 65.9 mmol) in N,N-dimethylformamide (80 ml) was stirred at 120° C. for 1.5 hours. After cooling as it was, the reaction solution was diluted with water and ethyl acetate, and the insoluble matters were filtered off. The aqueous layer in the filtrate was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in methanol, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.81 g, 63%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[CH:22]=[N:23][C:24]([N+:27]([O-])=O)=[CH:25][CH:26]=4)[CH:17]=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Sn](Cl)Cl>CCOC(C)=O.CCO>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[C:18]([O:20][C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[N:23][CH:22]=4)[CH:17]=[CH:16][N:15]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCC(c2ccc(-c3cc(Oc4ccc([N+](=O)[O-])nc4)ccn3)cc2)CC1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCC(c2ccc(-c3cc(Oc4ccc(N)nc4)ccn3)cc2)CC1
Temperature: 65 °C
Yield: 136 %

Procedure:
A solution of 2-(4-(1-methylpiperidin-4-yl)phenyl)-4-((6-nitropyridin-3-yl)oxy)pyridine (0.199 g, 0.510 mmol) in EtOAc (10 mL) and EtOH (10 mL) was treated with tin(II) chloride dehydrate (0.575 g, 2.55 mmol), heated at 65° C. for 4 h, then heated 75° C. overnight. Additional tin(II) chloride dehydrate (300 mg) was added, the mixture heated at 80° C. for 6 h, treated with another portion of tin(II) chloride dehydrate (300 mg) and heated at 80° C. for 3 days. Additional tin(II) chloride dehydrate (300 mg) was added and the mixture heated at 80° C. overnight. The mixture was cooled to RT, concentrated to dryness, treated with EtOAc and satd. NaHCO3, filtered through diatomaceous earth and the filter cake rinsed with EtOAc/THF. The filtrate was treated with solid NaOH (2 g) and NaCl until the aqueous layer was saturated, extracted with 3:1 EtOAc/THF (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (250 mg, >100%). MS (ESI) m/z: 361.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)c1ccnc(C(=O)CBr)c1
Product: COC(=O)Cc1c(C(=O)c2cc(C(C)(C)C)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-tert-butylpyridine (Preparation is described in Example 69).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH3:19][NH2:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:20][CH3:19])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CN
Solvent: O
Product: C=CCNc1nc(NC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 230 mg (0.87 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 902 mg (12.88 mmol) of a 40% aqueous methylamine solution was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 190 mg (yield: 84.2%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[N:19]1>>[N:18]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[N:19]1
Reactant: c1n[nH]c2c1CCCC2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(-n2ncc3c2CCCC3)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (76 mg, 0.293 mmol) and 4,5,6,7-tetrahydroindazole (44 mg, 0.360 mmol) similar to Example 166 and was isolated as a white solid (25 mg, 0.072 mmol, 25% %). 1H NMR (CDCl3) 9.68 (d, J=1.2 Hz, 1H), 8.75 (m, 2H), 8.40 (s, 1H), 8.07 (s, 1H), 7.45 (ddd, J=1.2, 5.1, 9.0 Hz, 1H), 2.73 (m, 4H), 1.88 (m, 4H).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])(=O)C.CO.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: CC(=O)OCC(C)(C)CS(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)CS(N)(=O)=O
Yield: 77.6 %

Procedure:
To a solution of 10.0 g of 3-acetoxy-2,2-dimethyl-1-propanesulfonamide in 80 ml of methanol was added 9.2 g of 28 W/W % sodium methoxide methanol solution at room temperature with stirring. After stirring for 30 minutes, the reaction mixture was concentrated to dryness, and the residue was subjected to a silica gel column chromatography, eluting with chloroform-methanol (9:1). The corresponding fractions were concentrated to obtain 6.2 g of 3-hydroxy-2,2,-dimethyl-1-propanesulfonamide.