Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1)#[N:2].[CH:24]([O:29][CH3:30])([O:27][CH3:28])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:30][O:29][C:24]1([O:27][CH3:28])[CH2:5][CH2:4][C:3]([C:1]#[N:2])([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7]1
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Yield: 99.1 %

Procedure:
A mixture of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.5 g, 1.6 mmol), trimethyl orthoformate (0.21 mL, 1.9 mmol) and a catalytic amount of p-toluenesulfonic acid in methanol (20 mL) was heated gently under an argon atmosphere for 2 h. The mixture was cooled, was partitioned between aqueous sodium carbonate and ethyl acetate, was extracted twice with ethyl acetate, the organic extract was dried (potassium carbonate) and the solvent was removed in vacuo to provide an oil (0.57 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a suspension of 2-bromo-4-(trifluoromethoxy)phenol (3 g, 11.7 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in N,N-dimethylformamide (35 mL) was added benzyl bromide (2.1 mL, 17.5 mmol) dropwise and stirred at room temperature for 16 hours. Reaction mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate:hexane (2:98, by volume) afforded the title compound, 3.3 g, 81% yield.
Reaction SMILES: [NH:1]1C2C(=CC(C#N)=CC=2)C=[CH:2]1.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](OC(F)(F)F)[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:2]#[N:1])[CH:22]=2)[N:17]([CH2:29][C:30]([OH:32])=[O:31])[CH:16]=1)(=[O:14])[CH3:13]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: CC(=O)c1cn(CC(=O)O)c2ccc(C#N)cc12

Procedure:
was prepared from 1H-indole-5-carbonitrile in a similar manner as described in Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. MS (LC/MS): 241.2 [M−H]−; 243.2 [M+H]+; tR (HPLC conditions a): 2.62 min.
Reaction SMILES: O.Cl.C[O:4][CH:5](OC)[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH:20](OC)[O:21]C)[N:13]=[C:12]([NH:25][CH2:26][CH2:27][CH2:28][CH:29]([O:32]C)OC)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:32][CH:29]1[CH2:28][CH2:27][CH2:26][N:25]1[C:12]1[N:13]=[C:14]([N:16]2[CH2:17][CH2:18][CH2:19][CH:20]2[OH:21])[N:15]=[C:10]([N:9]2[CH2:8][CH2:7][CH2:6][CH:5]2[OH:4])[N:11]=1
Reactant: COC(CCCNc1nc(NCCCC(OC)OC)nc(NCCCC(OC)OC)n1)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OC1CCCN1c1nc(N2CCCC2O)nc(N2CCCC2O)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Water (50 ml) containing 37 weight % hydrochloric acid (6 ml) was added in one portion to a stirred solution of the tris-(4,4-dimethoxybutylamino)-1,3,5-triazine of Example 1 (6.0 g; 0.0127 mole) in acetone (50 ml) under nitrogen. The reaction mixture was stirred at room temperature for four days and thereafter neutralized with solid potassium carbonate. The solution was then transferred to a separatory funnel and extracted with ethyl acetate (2×150 ml). The organic layer was separated, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to give 2,4,6-tris-(2-hydroxypyrrolidin-1-yl)-1,3,5-triazine as a solid (2.7 g; 64% isolated yield). The structure of the product was confirmed from the 1H NMR spectrum which exhibited the characteristic absorption for the --NCHO-- group at (δ) 5.6 (m, 1 H).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]nc(/C=C/c2ccc(Cl)cc2)cc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution (5 mL) of 3,4-bis(benzyloxy)-6-[(E)-2-(4-chlorophenyl)vinyl]pyridazine (150 mg) in dichloromethane was added a solution (770 μL) of 1M boron tribromide in dichloromethane at −78° C. and the mixture was stirred at 0° C. for 3 hr. Methanol was added to terminate the reaction, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and the obtained solid was washed with ethanol-water, collected by filtration and dried under reduced pressure to give 6-[(E)-2-(4-chlorophenyl)vinyl]-4-hydroxypyridazin-3(2H)-one (58 mg).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2([OH:22])[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH3:21])[N:15]=[CH:14][C:13]2=3)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:23].CC(O)C>>[NH2:23][C:7]1[C:6]2[N:5]([C:4]([C:12]3([OH:22])[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:3][C:2]=2[Br:1])[CH:10]=[CH:9][N:8]=1
Reactant: N
Reactant: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(Cl)nccn12
Solvent: CC(C)O
Product: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(N)nccn12
Temperature: 120 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (860 mg, 2.26 mmol) in NH3/i-PrOH (2N, 25 ml) was added in a sealed tube, and then stirred at 120° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated under reduce pressure. The residue was re-dissolved in DCM, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give 4-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (720 mg, 88%). MS-ESI (m/z): 363 (M+1)+ (Acq Method: 0-60AB_2 min; Rt: 0.98 min)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(N[C@H]1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(N[C@H]1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
The title compound was also prepared using the following procedures: To a solution of 87C (510 mg, 1.11 mmol) in THF/MeOH (2.1, 15 mL) was added phenylboronic acid (272 mg, 2.22 mmol), followed by K2CO3 (613 mg, 4.44 mmol) and PXPd (30 mg, 0.056 mmol). The reaction mixture was stirred at 60° C. for 2 h, then additional amount of phenylboronic acid (54 mg, 0.44 mmol) and PXPd (16 mg, 0.028 mmol) were added. After 2 h at 60° C., same amount of phenylboronic acid and PXPd were added again to the reaction mixture to push completion of the reaction. After stirring at 60° C. for one more hour, the reaction was allowed to cool to RT and concentrated. The residue was partitioned between water and CH2Cl2, and the aqueous phase extracted with CH2Cl2 (50 mL×2). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using chromatography (silica gel) eluting with EtOAc/hexane (0-60%) to afford the title compound (260 mg, 51%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[NH2:15][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][CH:10]=1)[NH:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCN
Reactant: Nc1cccc(Br)c1
Product: CCCCCCNc1cccc(N)c1
Yield: 80.1 %

Procedure:
Using the general procedure, 3-bromoaniline (172 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent afforded the desired product as a colorless oil (154 mg, 80% yield). Rf=0.4 (hexane/ethyl acetate=2:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].P(Br)(Br)[Br:25]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][Br:25])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1nnc(CO)n1-c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccc(Br)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 5, 5-bromo-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is treated with phosphorus tribromide in chloroform to give 5-bromo-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:21]1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:21]2[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=2)[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2nccc(C(F)(F)F)n2)CC1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane (1.0 mL) at room temperature was added 2-chloro-4-trifluoromethyl-pyrimidine (0.1 g, 0.55 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 150° C. in a microwave for 30 minutes, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate and hexane to provide (4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) n/z 395 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.48(d, 1H), 7.37-7.32 (m, 5H), 6.72 (d, 1H), 5.08 (s, 2H), 4.67 (bs, 1H), 4.22 (m, 2H), 3.49(m, 2H), 2.08 (m, 2H), 1.68-1.60 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:15]1([C:21]2[C:26]([C:27]3[CH:37]=[CH:36][C:30]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:38][C:39]1[C:43]([CH:44]=O)=[C:42]([CH3:46])[N:41]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[N:40]=1.[ClH:53]>C1COCC1>[ClH:53].[CH3:38][C:39]1[C:43]([CH2:44][N:18]2[CH2:19][CH2:20][N:15]([C:21]3[C:26]([C:27]4[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])=[CH:36][CH:37]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:17]2)=[C:42]([CH3:46])[N:41]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[N:40]=1
Reactant: CC(=O)NCc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1nn(-c2ccccn2)c(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3c(C)nn(-c4ccccn4)c3C)CC2)cc1
Reaction time: 3 h
Yield: 54 %

Procedure:
Add sodium triacetoxyborohydride (231 mg, 1.04 mmol) to a solution of N-[4-(3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl)-benzyl]-acetamide (215 mg, 0.69 mmol) and 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxaldehyde (208 mg, 1.03 mmol) in THF (3.5 mL). Maintain stirring for 3 hr. and quench by adding NaHCO3 (5 mL). Extract with DCM (3×10 mL) and discard the aq. phase filtering through an IST phase separator Frit®. Concentrate to dryness and purify by preparative HPLC then purify by SCX-2® ion exchange chromatography, eluting with 2 M NH3 in MeOH to give the free base. Prepare the hydrochloride salt by adding HCl and lyophilise the solution to give the title compound (200 mg, 54%). MS (ES): m/z=497 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1Br
Temperature: 90 °C

Procedure:
A stirred mixture of 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid, ethyl ester (28.8 g, 86 mmol) and aqueous sodium hydroxide (35 mL of 2 M) in ethanol (690 mL) is heated at 90° C. for 2 h. The cooled mixture is then acidified with hydrochloric acid (200 mL of 1.0 M) and the resulting precipitate is filtered off and dried to give 3'-bromo-4'-methoxy-[1,1'-biphenyl]-4-carboxylic acid as a colourless crystalline solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1.[C:20]([C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:2][O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:13]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])=[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]3[C:29](=[CH:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)[C:30]2=[O:31])=[CH:9][CH:10]=1
Reactant: CCCC(O)CNCc1ccc(C(=O)OC)cc1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 458, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzoic acid methyl ester hydrochloride and 2-benzoyl-4-chlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(#N)C.[NH2:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:24]2[N:23]=[C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:26](=[O:27])[C:25]=2[CH:29]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
To a mixture of 1.0 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and 10 ml of acetonitrile was added 0.60 g of 2-amino-5-chloro-3-methylbenzoic acid, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture, 0.46 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.92 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.28 ml of methanesulfonyl chloride was added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.98 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[N:27]1[N:28]=[C:29]([NH:32][CH:33]2[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:35][CH2:34]2)[NH:30][CH:31]=1.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:18])[N:32]([C@H:33]3[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:38]3)[C:29]3[N:28]([N:27]=[CH:31][N:30]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: CCOC(=O)C1CCC(Nc2nnc[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)OCC)CC2)c2ncnn12
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.5 g), ethyl 4-(4H-1,2,4-triazol-3-ylamino)cyclohexanecarboxylate (0.68 g) and N,N-diethylaniline (2.5 mL) was stirred at 180° C. for 16 hr. The obtained reaction mixture was diluted with ethyl acetate, washed 3 times with 1 N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 31%).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].C1COCC1.[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:54])=[O:53])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][NH:41][CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C=O>CO>[CH:10]1([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([C:49]([NH:51][S:52]([CH:55]4[CH2:57][CH2:56]4)(=[O:53])=[O:54])=[O:50])=[CH:21][C:22]=3[N:23]3[CH2:29][C:28]([C:30]([N:32]4[CH2:39][C:38]56[CH2:40][N:41]([CH3:1])[CH2:42][C:34]5([CH2:35][O:36][CH2:37]6)[CH2:33]4)=[O:31])=[CH:27][C:26]4[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:25]=4[C:24]=23)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1CC34CNCC3(COC4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C=C(C(=O)N1CC34COCC3(CN(C)C4)C1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A 1M solution of sodium cyanoborohydride in THF (0.15 mL, 0.15 mmol) was added to a solution of 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-ylcarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (Example 22) (10 mg, 0.015 mmol) and formaldehyde (37 wt. % in water) (0.01 mL, 0.1 mmol) in MeOH (1 mL) and the mixture was stirred at rt for 16 h. The reaction was concentrated, dissolved into MeOH, filtered and purified by preparative HPLC (H2O-MeOH with 0.1% TFA buffer) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((10-methyl-3-oxa-7,10-diazatricyclo[3.3.3.01,5]undec-7-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (7.9 mg, 9.4 μmol, 63% yield) as a bright yellow solid. LCMS: m/e 685 (M+H)+. LCMS retention time: 1.92 min. (Column: SunFire C18 5u 4.6×50 mm. Solvent A=90% Water/10% Acetonitrile/0.1% TFA. Solvent B=10% Water/90% Acetonitrile/0.1% TFA. Start % B=0. Final % B=100. Gradient Time=3 min. Flow Rate=4 mL/min.) 1H NMR (400 MHz, MeOD) δ ppm 8.09 (br s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.54 (br d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 7.07 (s, 1H), 5.22 (br d, J=14.8 Hz, 1H), 4.13-3.12 (m, 10H), 4.23 (br d, J=14.8 Hz, 1H), 3.90 (s, 3H), 2.97-2.76 (m, 5H), 2.15-1.67 (m, 6H), 1.52-1.07 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C1COCC1>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1Cl
Yield: 92.6 %

Procedure:
A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel® in 150 ml of MeOH and 200 ml of THF is hydrogenated in Parr apparatus for 4 hours, at 35° C. and under a pressure of 1.3 bar. The catalyst is filtered off over Celite® and the filtrate is concentrated under vacuum. 28 g of the expected product are obtained and are used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O-:29])=[O:28].[OH-].[K+]>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of ethyl (1RS, 2RS, 3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford the title compound (40 mg, 49%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1.[C:18](OCC)(=[O:21])[NH:19][NH2:20]>C(O)CCC>[CH3:8][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[N:4][N:3]2[C:18](=[O:21])[NH:19][N:20]=[C:2]2[CH:7]=1
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: Cc1cc2n[nH]c(=O)n2nc1-c1cccc([N+](=O)[O-])c1

Procedure:
A mixture comprising 7.0 g. of 3-chloro-5-methyl-6-(m-nitrophenyl)-pyridazine (U.S. Pat. No. 4,092,311), 5.8 g. of ethyl carbazate and 60 ml. of butanol is refluxed for 18 hours, then cooled in an ice bath and filtered. The solid is air dried giving 2.96 g. of the desired product as a yellow solid, m.p.>300° C.
Reaction SMILES: [NH2:1][C:2]([C:6]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:8][CH2:7]1)([CH3:5])[CH2:3][NH2:4].O.[ClH:17]>>[ClH:17].[ClH:17].[NH2:1][C:2]([C:6]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([CH3:5])[CH2:3][NH2:4]
Reactant: CC(C)(C)OC(=O)C1(C(C)(N)CN)CC1
Agent: Cl
Solvent: O
Product: CC(N)(CN)C1(C(=O)O)CC1
Reaction time: 0.5 h

Procedure:
0.82 g (3.83 mmol) of the crude tert-butyl 1-(1,2-diamino-1-methyl ethyl)-1-cyclopropanecarboxylate was dissolved in concentrated hydrochloric acid (5 mL) at room temperature, and the solution was stirred at the same temperature for 30 minutes. After adding water to the reaction solution, the solvent was removed by distillation under reduced pressure. The residue was azeotropically distilled with ethanol (twice) to obtain 0.82 g (3.55 mmol, 93%) of the crude target compound as a pale yellow foam solid. The thus obtained crude product was used in the subsequent reaction with no further purification.