Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[CH2:16]([N+:23](C)(C)C)[C:17]1C=CC=C[CH:18]=1>C(#N)C=C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:17][C:16]#[N:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [OH-]
Solvent: C=CC#N
Product: N#CCCOc1cccc(CN2CCCCC2)c1

Procedure:
A solution of 3-(1-piperidinylmethyl)phenol (26 g), acrylonitrile (100 ml) and benzyltrimethylammonium hydroxide (40% methanolic solution, 5 ml) was heated at reflux for 40 h. The mixture was evaporated in vacuo, diluted with ether (300 ml) and filtered. The filtrate was washed with 2N sodium hydroxide, water and distilled to give the title compound as a colourless oil (17.5 g) b.p. 170°, 0.07 mm; tlc system B, Rf 0.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=1[C:55]([CH3:58])([CH3:57])[CH3:56].[F-].[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:41]2[C:46]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][C:44]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:43][C:42]=2[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(Br)c(C(C)(C)C)c1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2c(C(C)(C)C)cc(C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of racemic 3-(4-{5,5,5-Trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester (0.300 g, 0.550 mmol) in toluene (3.0 mL) is added palladium tetrakis triphenylphosphine (0.0316 g, 0.030 mmol), 2-bromo-1,3,5-tri-tert-butyl-benzene (0.353 g, 1.09 mmol), and potassium fluoride (0.063 g, 1.09 mmol). The reaction is purged with nitrogen three times and heated to reflux under nitrogen. At reflux, water (1.0 mL) is added to the reaction and the reaction is allowed to reflux under nitrogen. The reaction is monitored by HPLC, and upon completion, allowed to cool to room temperature. The reaction is diluted with ethyl acetate and celite is added, followed by water. This mixture is then filtered through a pad of celite. The solution is poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is purified by flash column chromatography (0.333 g, 0.500 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[C:20]1[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OC1C=CC([N+]([O-])=O)=CC=1C(OCC1C=CC=CC=1)=O)(=O)=O>>[CH2:1]([O:8][C:9]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[C:20]1[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1-c1ccc([N+](=O)[O-])cc1C(=O)OCc1ccccc1
Agent: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Product: Nc1ccc(-c2ccccc2C(=O)O)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To a solution of 2′-benzyloxycarbonyl-4′-nitro-2-biphenylcarboxylic acid (2.08 g) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5, using Benzyl 2-trifluoromethylsulfonyloxy-5-nitrobenzoate, in concentration hydrochloric acid-ethanol (5:3, 8 ml), a solution of Tin (II) chloride dihydrate (3.7 g) in ethanol (5 ml) was added. The mixture was stirred for 1 hour at room temperature. 2N aqueous solution of sodium hydroxide was added to the reaction solution, the solution was extracted with ethyl acetate (2 times). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Chloroform:Methanol:Water=9:1:0.1→8:2:0.2) to give the title compound (1.07 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(F)c(F)c1Cl
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(F)c(F)c1Cl
Reaction time: 40 h
Yield: 52.3 %

Procedure:
To a mixture of 2-chloro-3,4-difluorobenzoic acid (2.50 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.99 g), 1-hydroxybenztriazole (2.39 g) and N,N-dimethylformamide (72 mL) was added 28% aqueous ammonia (1.6 mL) at room temperature, and the mixture was stirred for 40 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was washed with dichloromethane to give the title compound as a solid (yield: 1.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[SH:19][C:20]1C=C[C:23]([B:26]([OH:28])[OH:27])=[CH:22][CH:21]=1>CC(O)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:21]2[CH:22]=[C:23]([B:26]([OH:28])[OH:27])[S:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(c2ccc(OC)cc2)c2csc(B(O)O)c2)cc1
Temperature: 60 °C

Procedure:
4,4′-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in 20 mL AcOH and heated at 60° C. for 1 h. Solvent was evaporated and the residue was dried under high vacuum. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14].C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][CH3:16])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Temperature: 60 °C
Reaction time: 23 h
Yield: 88.2 %

Procedure:
To 2,4-dichloropyrimidine (250.0 mg, 1.678 mmol) and 3-amino-N-methylbenzamide (252 mg, 1.678 mmol) in 2-propanol (8390 μL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (585 μL, 3.36 mmol). The resulting reaction mixture was heated at 60° C. for 22 h, then to 70° C. for 23 h, then 80° C. for 3 days, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (389.0 mg).
Reaction SMILES: [Br:1][C:2]1([Cl:10])[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH2:3]1.[ClH:11].[OH-].[Na+]>C1COCC1>[ClH:10].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: N#CC1=CCC(Cl)(Br)C=C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1ccc(Br)cc1Cl

Procedure:
46.2 ml of borane-THF complex are provided under ice cooling. A solution of 2.0 g of 4-bromo-4-chlorobenzonitrile in 240 ml of THF is added slowly. The reaction mixture is then heated for 1 h under reflux, cooled and 20 ml of 1N hydrochloric acid are added dropwise while cooling on ice. The mixture is heated under reflux for 1 h and left to cool. For the work-up the solution is adjusted to an alkaline pH with a 1N sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. 6 ml of hydrochloric acid in dioxane (4N) are added and the precipitated hydrochloride is collected by suction filtration. 1.3 g of product are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1.C[Si](C)(C)Cl.[OH:32]O.O>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:11](=[O:32])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1
Reactant: CN(C)CCN1C(=O)C(=Cc2ccc(Cl)cc2Cl)Sc2ccccc21
Reactant: OO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCN1C(=O)C(=O)C(c2ccc(Cl)cc2Cl)Sc2ccccc21
Reaction time: 0.5 h
Yield: 105 %

Procedure:
The solution of 2-(2,4-dichlorophenylmethylidene)-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazine-3(4H)-one hydrochloride (1 g) in 10 ml of chloroform was cooled below 0° C. and added with trimethylchlorosilane (2 ml), and then added with 30% hydrogen peroxide (0.29 g) for 30 minutes. The solution was stirred for 30 minutes below 0° C., and added with 1 ml of water. After further stirring for 1 hour at room temperature, 10 ml of water was added to the reaction mixture. The aqueous phase of the mixture was adjusted to a pH within 8-9 and the chloroform layer was separated from the mixture. The remaining aqueous phase was extracted with 10 ml of chloroform. The chloroform solutions wee combined, dried and evaporated under reduced pressure. The oily residue was purified by silicagel chromatography to give 2-(2,4-dichlorophenyl)-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-3,4(5H)-dione (1.0 g) as oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:45][C:46]([NH:48][CH:49]1[C:59]2[CH:60]=[C:61](O)[CH:62]=[CH:63][C:58]=2[C:57]2[C:52](=[CH:53][C:54]([O:69][CH3:70])=[C:55]([O:67][CH3:68])[C:56]=2[O:65][CH3:66])[CH2:51][CH2:50]1)=[O:47]>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C:61]1[CH:62]=[CH:63][C:58]2[C:57]3[C:56]([O:65][CH3:66])=[C:55]([O:67][CH3:68])[C:54]([O:69][CH3:70])=[CH:53][C:52]=3[CH2:51][CH2:50][C@H:49]([NH:48][C:46](=[O:47])[CH3:45])[C:59]=2[CH:60]=1)=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 3-{[(2R)-2,6-di(tertbutoxycarbonylamino)hexanoyl]amino}propanoic acid (2) (0.178 g; 0.5 mmol), DCCI (0.124 g; 0.6 mmol), DMAP (0.013 g; 0.1 mmol) and N-acetyl-colchicinol (0.25 g; 1.2 mmol) in dichloromethane was stirred under argon atmosphere at ambient temperature for 5 hours. After filtration of the insoluble material the residue was purified by flash chromatography eluting with dichloromethane/ethanol (95/5) to give (1).
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)NCCNc2ccccn2)co1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(Cc1nc(C(=O)NCCNc2ccccn2)co1)c1ccccc1
Reaction time: 24 h
Yield: 32.9 %

Procedure:
To a solution of ethyl(±)-3-phenyl-4-[4-[[[2-(pyridin-2-yl)amino-1-ethyl]amino]carbonyl]-1,3-oxazol-2-yl]butanoate (157 mg, 0.37 mmole) in 1:1 THF/H2O (4 mL) was added 1.0 N LiOH (0.56 mL, 0.56 mmole). After 24 hr, the mixture was washed with Et2O (2×2 mL), and the pH of the aqueous layer was adjusted to 6 using 10% HCl. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 50 mL 10% CH3CN/H2O). Fractions containing the product were pooled and lyophilized to give the title compound (48 mg, 33%) as a white powder: MS (ES) m/e 395 (M+H)+. Anal. Calcd for C21H22N4O4. 0.75 HCl: C, 59.80; H, 5.44; N, 13.28. Found: C, 59.89; H, 5.50; N, 12.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]3[CH2:25][O:24]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH:23]([OH:24])[CH2:25][N:29]3[CH2:30][CH2:31][CH2:32][CH:27]([OH:26])[CH2:28]3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCCNC1
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC2CO2)CC1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(O)CN2CCCC(O)C2)CC1

Procedure:
In analogy to the procedure described for example 167D, (rac)-1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxiranyl-ethyl)-[1,4]diazepan-5-one and 3-hydroxypiperidine gave the title compound as yellow oil. MS: 484.2 (MH+, 2Cl).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18].O>CN(C=O)C.C(Cl)Cl>[CH:17]([N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:19])[CH3:18]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.7 %

Procedure:
To a stirred of solution of 3-methyl-4-nitro-1H-pyrazole (0.3 g, 2.4 mmol) in DMF (10 mL) was added potassium carbonate (0.4 g, 2.9 mmol) and 2-iodopropane (0.72 mL, 7.2 mmol). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 mL) and extracted into ether (4×30 mL). The combined ethereal extracts were dried (MgSO4) and the solvent removed under vacuum to give a pale yellow oil. Several purifications were performed via column chromatography (SiO2; 200 equiv. 100% DCM) to give 1-isopropyl-3-methyl-4-nitropyrazole (11 mg, 93% isomeric purity). This was combined with another batch (110 mg, purified identically).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Br:21]Br>ClCCl>[Br:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:8]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:9]=1
Reactant: BrBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(C)cnc32)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cc(C)cnc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1.9 g, 6.62 mmol) in dichloromethane (40 mL) was treated dropwise with a solution of bromine (0.678 mL, 13.24 mmol) in dichloromethane (3 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was partitioned between dichloromethane (150 mL) and a 1:1 mixture of a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of Na2S2O3 (250 mL). The organic phase was separated and the aqueous phase was re-extracted twice with DCM (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give the desired compound as an off-white solid (2.381 g, 99% yield). 1H NMR (DMSO-D6, 400 MHz) δ 2.34 (3H, s), 2.39 (3H, s), 7.42 (2H, d), 7.75 (1H, s), 7.99 (2H, d), 8.14 (1H, s), 8.21 (1H, s); MS (ES+) 365.
Reaction SMILES: OCCN1CC2C(C2NC(=O)OC(C)(C)C)C1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:30][S:31]([O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:39][CH2:38]1)(=[O:33])=[O:32].S([O-])(=O)(=O)C>C(Cl)(Cl)Cl>[CH3:30][S:31]([O:34][CH2:35][CH2:36][N:37]1[CH2:38][CH:39]2[CH:41]([CH:40]2[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42]1)(=[O:32])=[O:33]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1C2CN(CCO)CC21
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1C2CN(CCOS(C)(=O)=O)CC21
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl [3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate (Intermediate 96) (376 mg, 1.55 mmol) and triethyl amine (0.283 mL, 3 mmol) in anhydrous chloroform (15 mL) was added at 0° C. methanesulfonyl chloride (228 mg, 3 mmol) via syringe. The reaction was allowed to warm to room temperature over 1 hr and worked up as described for Intermediate 6. The crude mesylate was used for the next step without delay.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH3:30]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][N:8]2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[O:18])=[CH:3][C:2]=1[CH3:30]
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(OC)c1nc2c(cc1C)CCCN2C(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-bromo-7-(dimethoxymethyl)-N-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2D, 50 mg, 0.105 mmol), trimethylboroxine in (50% in THF, 39.6 mg, 0.158 mmol), Na2CO3 (2 M in water, 0.053 ml, 0.105 mmol), PdCl2(PPh3)2 (7.38 mg, 10.52 μmol) and DME (1 ml) were charged into a sealed vial under argon. The mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted in EtOAc and washed 2× with water and 1× with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 58:42). The product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 1) tR 1.37 min; ESI-MS 411.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:13].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C)C=O>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][C:2](=[O:13])[N:3]([CH2:21][CH2:22][CH2:23][Cl:24])[C:4]1=[O:12]
Reactant: O=C1Cc2ccccc2CC(=O)N1
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Cc2ccccc2CC(=O)N1CCCCl

Procedure:
Here, 1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione (3.5 g, 0.020 mol) is suspended in dimethylformamide (30 ml) and potassium tert. butoxide (2.5 g) is added with stirring. After 10 minutes the resulting solution is added dropwise, while cooling with ice, to 1-bromo-3-chloro-propane (3.5 ml) in dimethylformamide (20 ml). After one hour it is poured onto ice water. After a short time the greasy precipitate crystallizes. The precipitate is suction filtered, dissolved in acetone, reprecipitated with water, suction filtered and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][C:7]=1[CH3:22].[CH2:23]([NH:27][CH2:28][CH2:29][CH2:30]C)[CH2:24][CH2:25]C>>[CH2:23]([N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][C:7]=1[CH3:22])[CH2:28][CH2:29][CH3:30])[CH2:24][CH3:25]
Reactant: CCCCNCCCC
Reactant: Cc1cc(-c2cn3cccc(C)c3n2)ccc1OCCCCl
Product: CCCN(CCC)CCCOc1ccc(-c2cn3cccc(C)c3n2)cc1C

Procedure:
The product of Step C (3.0 g) and dibutylamine (10.0 mL) were heated at reflux temperature for 18 hours. The reaction was evaporated and the residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][O:27][CH3:28])[CH2:23][CH2:22][C:21]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.[C:38](OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][O:27][CH2:28][CH3:38])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3CCOC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCOCC)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In ethyl acetate (28 ml) was dissolved tert-butyl 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (1.4 g). To the solution was added 4N hydrochloric acid/ethyl acetate (14 ml) at room temperature, and the mixture was stirred at 60° C. for 2 hours. After cooled to room temperature, an aqueous saturated solution of sodium hydrogen carbonate was added to adjust pH to approximate 5. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-ethoxyethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.61 g, 49%).