Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:27][C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:27][C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCC2c3ccccc3Oc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCC2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 2-ethoxy-3-{4-[2-(9H-xanthen-9-yl)ethoxy]phenyl}propionate (1.8 g, 4.03 mmol) in ethanol (15 ml) was added a 15% solution of NaOH (4 ml), and the mixture was stirred at room temperature for 5 h, then left to stand overnight. The resulting solution was evaporated, water (50 ml) was added, the mixture was acidified with 15% hydrochloric acid to pH 2, and the products extracted into Et2O (4×30 ml). The combined extracts were washed with water (30 ml), brine (15 ml), dried (MgSO4) and evaporated to give the title compound as an oil: 1.3 g (77.1%).
Reaction SMILES: C([NH:11][C@H:12]([C:14](O)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[NH2:44][C@H:45]([C:51]([OH:53])=[O:52])[CH2:46][CH2:47][C:48](=[O:50])[NH2:49].[OH-].[Na+].Cl>O.C1(C)C=CC=CC=1>[NH2:11][C@H:12]([C:14]([NH:44][C@H:45]([C:51]([OH:53])=[O:52])[CH2:46][CH2:47][C:48](=[O:50])[NH2:49])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 3 h
Yield: 48 %

Procedure:
In a round bottom flask, add in 10 mmol each of carbobenzoxy-alanine (Z-Ala), triphenylphosphine and hexachloroethane respectively, and then 30 ml of toluene. After reacting at 0° C. for 3 h., drop it into a liquid mixture containing 25 mmol of glutamine and 20 ml of water. While reacting, regulate pH to 12 with sodium hydroxide, the reaction temperature is 15° C., the reaction time after dropping is 1.5 hours. And then acidify it to pH=2.5 with dilute hydrochloric acid. The aqueous phase, after concentrated, reacts with hydrogen gas in methanol at room temperature for 15 hours. The product L-Ala-L-Gln with a yield of 48% is obtained.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1)=O)C.[BH4-].[Li+].CO>O1CCCC1>[OH:3][CH2:4][CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[S:7]1
Reactant: CCOC(=O)C1CNc2ccccc2S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CNc2ccccc2S1

Procedure:
1.6 g of 2(R,S)-ethoxycarbonyl-3,4-dihydro-2H1,4-benzothiazine are reacted with 1.06 g of lithium borohydride in 20 ml of tetrahydrofuran. After addition of 10 ml of methanol, the mixture is concentrated and the residue is purified by means of FC over 80 g of silica gel (mobile phase S). This gives the title compound: Rf (S)=0.29.
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][O:4][CH2:3]2.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1.C(N(CC)CC)C.C(Cl)Cl>C(O)C>[Cl:10][C:11]1[N:12]=[C:13]([N:9]2[CH:6]3[CH2:7][CH2:8][CH:2]2[CH2:3][O:4][CH2:5]3)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: C1CC2COCC1N2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A slurry of 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.1064 g, 0.7112 mmol) in ethanol (2 mL) was added to 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (0.1 g, 0.3556 mmol). triethylamine (0.250 mL, 1.778 mmol) was added and the mixture was stirred overnight at room temperature. DCM (2 mL) was added to form a complete solution and the mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in DCM (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with DCM (2×2 mL). The combined organic layers were evaporated to give a brown oil. Mass: 162 mg. This was purified by silica chromatography (10 g cartridge; eluent petrol/ethyl acetate 0 to 15%; all output collected) and the second eluting peak isolated to give 8-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane as a white solid (111 mg). LCMS: RT=4.95 min. M+1=358.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[NH:5][C:6]([C:10]([O:12]CC)=[O:11])=[C:7]([CH3:9])[N:8]=1.CO>C1COCC1>[CH3:3][C:4]1[NH:5][C:6]([C:10]([OH:12])=[O:11])=[C:7]([CH3:9])[N:8]=1
Reactant: CCOC(=O)c1[nH]c(C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)O)[nH]1
Temperature: 70 °C
Yield: 99 %

Procedure:
Lithium hydroxide (1.6 mL, 1.6 mmol, 1 M in H2O) was added to a solution of ethyl 2,4-dimethyl-1H-imidazole-5-carboxylate (54 mg, 0.32 mmol) in THF:MeOH (4.8 mL/1.6 mL). The reaction mixture was heated at 70° C. for 4 h. The solvent was evaporated and dried in vacuo to give the title compound (mg, >99%) as a white solid which was directly used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]2[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]3[S:13][CH2:12][CH:11]([CH3:14])[O:10][C:9]=32)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:14][CH:11]1[O:10][C:9]2[C:15]3[C:5]([C:6](=[O:18])[C:7](=[O:17])[C:8]=2[S:13][CH2:12]1)=[CH:4][CH:3]=[C:2]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=3
Reactant: C1CCNCC1
Reactant: CC1CSC2=C(O1)c1cc(Br)ccc1C(=O)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CSC2=C(O1)c1cc(N3CCCCC3)ccc1C(=O)C2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 24.5 %

Procedure:
To a solution of 9-bromo-2-methyl-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.1 g, 0.31 mmol) in 1,4-dioxane (1.0 mL) was added piperidine (0.061 mL, 0.616 mmol) and potassium carbonate (0.043 g, 0.308 mmol). The reaction mixture was stirred at 90° C. for 18 hours. The resulting mixture was filtered and solvent was removed under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 50% EtOAc in hexanes) to give the product as a purple solid (0.025 g, 25%). M.p.=225-226° C.; 400 MHz 1H NMR (CDCl3) δ: 7.91 (d, J=8.8, 1H), 7.09 (d, J=2.8, 1H), 6.72 (m, 1H), 4.62 (m, 1H), 3.49 (m, 4H), 3.07 (d, J=13.6, 1H), 2.88 (m, 1H), 1.71 (br. s, 6H), 1.60 (d, J=6.4, 3H); LCMS: 330 [M+H].
Reaction SMILES: NC1C(C=[N:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=NC(Cl)=C(Cl)N=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.NN>O1CCCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([NH:12][NH2:11])(=[O:14])=[O:15])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2nc(Cl)c(Cl)nc2N)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NN)cc1

Procedure:
p-Toluenesulfonic acid 2-[(3-amino-5,6-dichloropyrazinyl)methylene]hydrazide by the reaction of p-toluenesulfonyl chloride with hydrazine in tetrahydrofuran to form p-toluenesulfonylhydrazine, followed by the reaction of the latter with 3-amino-5,6-dichloropyrazinaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[CH3:1][C:2]1[C:3](/[CH:4]=[CH:20]/[N+:17]([O-:19])=[O:18])=[CH:6][CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccc(C=O)c1C
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cccc(/C=C/[N+](=O)[O-])c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-3-(methyloxy)benzaldehyde (available from Allichem Product List; 20.0 g; 133 mmol) in nitromethane (400 ml) was added ammonium acetate (6.16 g; 80.0 mmol) and the resulting orange mixture was stirred for 1 h at 100° C. then cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (×2) and brine, and the organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Trituration with dichloromethane/ether gave the title compound as a yellow solid (6.60 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26]([OH:28])=O.[N-:29]1C=CN=[CH:30]1.CN>ClCCl>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]1[C:26](=[O:28])[NH:29][CH3:30]
Reactant: c1c[n-]cn1
Reactant: Cc1cc(C2=NN(C(=O)O)C(C)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: CN
Solvent: ClCCl
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C)OCO3
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A mixture of 2.17 g (5.0 millimoles) of (±)-7,8-dihydro-8-methyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3dioxolo[4,5-h][2,3]benzodiazepine-7-carboxylic acid-imidazolide, 75 ml of dichloro methane and 15 ml of a 33% ethanolic methyl amine solution is stirred for 3 hours. The reaction mixture is evaporated in vacuo and the residue is suspended in 75 ml of water. The crude product is filtered off, washed with 25 ml of water, dried and recrystallized from 25 ml of ethanol. Thus 1.68 g of the desired compound are obtained, yield 85%, mp.: 221–229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23][CH2:24][CH2:25]P(=O)(O)O)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.NC1C=[CH:35][C:34]([P:37](=[O:44])([O:41]CC)[O:38]CC)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23][C:24]2[CH:32]=[CH:33][C:34]([P:37](=[O:38])([OH:44])[OH:41])=[CH:35][CH:25]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCP(=O)(O)O)c2)C1
Reactant: CCOP(=O)(OCC)c1ccc(N)cc1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Nc3ccc(P(=O)(O)O)cc3)c2)C1

Procedure:
Compound 2 was prepared in an analogous manner to that of Compound 1 using diethyl 4-aminophenylphosphonate (Intermediate 2.2) as the amine. 1H-NMR (300 MHz, CD3OD, ppm): 7.86 (d, 1H), 7.69 (m, 3H), 7.55 (m, 3H), 7.21 (m, 2H), 6.73 (s, 1H), 4.70 (m, 2H), 4.48 (d, 1H), 3.79 (m, 1H), 3.46 (m, 1H), 3.09 (s, 3H). MS (ES, m/z): 527 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[S:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=O>>[CH2:1]([NH:3][CH2:9][C:5]1[S:4][CH:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1nccs1
Product: CCNCc1nccs1

Procedure:
prepared by reaction of ethylamine with thiazole-2-carbaldehyde
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.128 mL, 0.938 mmol) was added to tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.395 g, 0.782 mmol) and K2CO3 (0.130 g, 0.938 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 2 hours. Ether (30 mL) and water (10 mL) were then added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.33 g, 68%) as a solid. 1H NMR (400 Hz, CD2Cl2) δ 8.23 (s, 1H), 7.44 (m, 3H), 7.33 (d, J=8.8 Hz, 2H), 7.26 (m, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.59 (s, 2H), 3.76 (s, 3H), 3.55 (m, 4H), 2.86 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].C[N:17]([CH3:20])[CH:18]=O>>[CH3:6][C:3]1[C:4]2[N:5]=[CH:18][N:17]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[C:20]=2[CH:8]=[CH:9][CH:2]=1
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc2c1ncn2-c1ccccc1C#N
Reaction time: 20 h

Procedure:
The title A compound (133 mg, 1.01 mmol), 2-fluorbenzonitrile (164 μL, 1.51 mmol) and finely ground potassium carbonate (279 mg, 2.02 mmol) were combined in 1 mL of N,N-dimethylformamide and heated to 80°. After stirring for 20 hours, the dimethylformamide was removed in vacuo and the brown solid residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed. The residue was purified by flash chromatography (20 g silica gel, eluted with ethyl acetate, hexane) to provide 160 mg of the title B compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([N+:47]([O-])=O)[CH:44]=[CH:43][C:42]=2[Cl:50])[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[NH2:47][C:45]1[CH:44]=[CH:43][C:42]([Cl:50])=[C:41]([N:7]2[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[S:23](=[O:34])(=[O:35])[NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[CH:15][CH:16]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6]2)[CH:46]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 92.9 %

Procedure:
A mixture of 450 mg (0.612 mmol) of ethyl 3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxylate (from Step H), 50 mg of platinum oxide and 80 mL of ethanol was shaken with hydrogen at 3-4 atm for 1.25 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to yield 401 mg (93%) of the title compound as a tan solid, mp>75° C. (gradual); nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 705 (M+1)+. 400 MHz 1H NMR (DMSO-d6) δ0.81 (t, J=7.4 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H), 1.25 (m, 2H), 1.48 (m, 2H), 2.49 (t, 2H, partially obscured by DMSO peak), 4.0-4.2 (m, 4H), 5.5 (v br m, 2H), 6.64 (m, 2H), 7.1-7.4 (m, 8H), 7.47 (m, 2H), 7.6-7.75 (m, 2H), 8.16 (dd, J=8.0, 1.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[CH2:11]([O:13][C:14](=O)[CH:15]=[C:16](OCC)[O:17]CC)[CH3:12]>C(O)(=O)C>[CH2:11]([O:13][C:14]1[CH2:15][C:16](=[O:17])[NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[N:1]=1)[CH3:12]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: CCOC(=O)C=C(OCC)OCC
Solvent: CC(=O)O
Product: CCOC1=Nc2cc(F)c(F)cc2NC(=O)C1
Temperature: 140 °C
Yield: 80.7 %

Procedure:
To a solution of 1,2-diamino-4,5-difluorobenzene (4.0 g, 27.75 mmol) in xylenes (50 mL) at 140° C. was added acetic acid (200 μL) followed by a solution of 3,3-diethoxyacrylic acid ethyl ester (5.22 g, 27.75 mmol) in xylenes (25 mL) over 1 hour. The reaction was heated at 140° C. for 2 hours, was cooled to room temperature, and was concentrated. The residue was triturated in hexanes to provide 5.38 g of 4-ethoxy-7,8-difluoro-1,3-dihydro-benzo[b][1,4]diazepin-2-one. 1H NMR (CDCl3) δ 7.05 (q, 1H), 6.87 (q, 1H), 4.29 (q, 2H), 3.18 (s, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:2]2[CH:3]=[CH:4][CH:10]=[CH:11][CH:12]=2)[CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=C(O)CC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 3,4-dichlorocinnamic acid (50 g, 0.23 mole), benzene (150 mL) and concentrated sulfuric acid (100 mL) was stirred (using air driven overhead stirrer) in a 500 mL 3-neck round bottom flask while maintaining a reaction temperature of 85-95° C. The progress of the reaction was followed by HPLC. When the level of 3,4-dichlorocinnamic acid was <1% by HPLC (approximately 24 h), the reaction mixture was cooled to room temperature, then slowly poured into ice (300 g). The mixture was stirred for 30 min. then transferred into a 2 L separatory funnel. The organic layer was separated from the aqueous layer, and the aqueous layer was extracted with ethyl acetate (2×300 mL). The organic layers were combined, washed with water (5×500 mL) and brine (2×400 mL), then concentrated under reduced pressure. Ethyl acetate (500 mL) was added to the concentrate and the solution was evaporated to dryness. The product was dried under high vacuum at room temperature for 24 h. The desired carboxylic acid was obtained as a thick oil (65.8 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[N:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[N:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][C:3]=1[CH3:12]
Reactant: Nc1ccc(-c2cccnn2)cn1
Reactant: Cc1cc(CC(=O)O)cnc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(CC(=O)Nc2ccc(-c3cccnn3)cn2)cnc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 86-7 (241 mg, 1.3 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (224 mg, 1.3 mmol), 1,3-dicyclohexylcarbodiimide (325 mg, 1.6 mmol) and 4-(dimethylamino)pyridine (26 mg, 0.26 mmol) in DMF (6 mL) was stirred at room temperature for 10 hours. The reaction mixture was filtered to remove the solid and the filtrate was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, eluted with 5% methanol in dichloromethane to give 2-(6-chloro-5-methylpyridin-3-yl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 145-4 as pale yellow solid. MS m/z 340.2 (M+1)
Reaction SMILES: CON(C)[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19]1([CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]([Mg]Br)[CH:20]=1.Cl.O>C1COCC1.C(OCC)(=O)C>[C:19]1([CH3:27])[CH:24]=[CH:23][CH:22]=[C:21]([C:4](=[O:17])[CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:20]=1
Reactant: CON(C)C(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cccc([Mg]Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(=O)CCc2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 82.1 %

Procedure:
To a solution of 0.4 g (1.5 mmol) N-Methoxy-N-methyl-3-(4-trifluoromethyl-phenyl)-propionamide in 7 mL THF under argon at 0° C., was added dropwise 3.062 ml (3.1 mmol) m-Tolylmagnesiumbromid (1M in THF). The reaction mixture was stirred for 15 minutes at 0° C. and at RT for 50 minutes, cooled to 0° C. and acidified with 1N HCl to pH 1-2. Water and ethyl acetate were added and the water phase was extracted twice with ethyl acetate. The organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified with flash column chromatography on silica gel eluting with a gradient formed from heptane and ethylacetate to provide 0.36 g (81%) of title compound as colorless oil. MS (m/e): 293.0 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH3:6][S:7](Cl)(=[O:9])=[O:8].C(N(CC)CC)C>CCOCC>[CH3:6][S:7]([O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCC1CC1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
Cyclopropylcarbinol (27.4 g; 0.373 mol) and methanesulfonyl chloride (47.56 g; 0.407 mol) in dry ether (250 ml) was cooled to -20° C. under dry nitrogen. Triethylamine (59 ml; 0.42 mol) is added dropwise over 45 min with external cooling so that the reaction temperature remained below -15° C. The reaction mixture was allowed to warm to room temperature over 2 h and then filtered. The solid material is washed with ether. The solutions were combined and evaporated, to afford crude cyclopropylmethyl methanesulfonate (58.36 g) as a pale yellow liquid, which was used without further purification. NMR - d(CDCl3 ; 60 MHz) 0.3-1.5 (5H, m), 3.0 (3H, s) and 4.0 (2H, d, J=7 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:19])[S:9][C:10]=1[C:11](=[O:16])N(OC)C.[CH2:26]([Mg]Br)[CH2:27][CH3:28].[Cl-].[NH4+]>C1COCC1>[C:11]([C:10]1[S:9][C:8]([NH:17][C:18]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:19])=[N:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:16])[CH2:26][CH2:27][CH3:28]
Reactant: CCC[Mg]Br
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Compound 98 (200 mg, 0.559 mmol) was suspended in THF (5 mL), and a 1.01 mol/L solution of propylmagnesium bromide (2.00 mL, 2.02 mmol) in THF was added thereto under ice-cooling, followed by stirring for 1 hour at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford the entitled Compound 382 (76.3 mg, 40%) as a yellowish green solid.