Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18](O)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.[C:39]([NH:46][CH2:47][CH2:48][CH2:49][NH2:50])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O.CN1C(=O)CCC1.O>[C:42]([O:41][C:39](=[O:40])[NH:46][CH2:47][CH2:48][CH2:49][NH:50][CH:18]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=1)[CH2:19][CH3:20])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCC(O)c1nn2cccc2c(=O)n1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.2 %

Procedure:
To a solution of (±)-3-benzyl-2-(1-hydroxy-propyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (0.70 g, 2.47 mmol) in methylene chloride (20 mL) at 0° C. was added triethylamine (517 μL, 3.71 mmol) followed by methanesulfonyl chloride (290 μL, 3.71 mmol). The reaction was stirred at room temperature for 45 min and was then diluted methylene chloride (10 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude mesylate was treated with N-BOC-1,3-diaminopropane (Fluka, 1.29 g, 7.41 mmol) and NMP (20 mL) at 75° C. for 14 h. After cooling to room temperature, the reaction was diluted with saturated NaHCO3 solution (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with 10% LiCl solution (30 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:1) gave the title compound as a colorless viscous oil (610 mg, 61%): 1H NMR (CDCl3) δ 7.25 (m, 6H), 7.01 (m, 1H), 6.47 (m, 1H), 5.66 (d, 1H, J=16.2 Hz), 5.04 (brs, 1H), 4.85 (d, 1H, J=16.1 Hz), 3.48 (m, 1H), 2.91 (m, 2H), 2.42 (m, 1H), 1.96 (m, 1H), 1.64 (m, 2H), 1.34 (s, 9H), 1.28 (m, 2H), 0.86 (t, 3H, J=7.28 Hz); 13C NMR (CDCl3) δ 156.3, 155.7, 151.6, 137.1, 129.4, 128.1, 126.8, 121.3, 118.4, 111.2, 109.2, 79.3, 59.9, 45.8, 44.5, 39.7, 29.8, 28.8, 28.6, 11.2; MS (ESI+) 440.29 (M++H).
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([OH:22])=O)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:25](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>C1COCC1.O.C(OC(=O)C)C>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[C:20]([NH2:25])=[O:22])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Temperature: 0 °C

Procedure:
To a suspension of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid G2 (0.25 mmol) in THF (3 mL), DIEA (0.75 mmol) was added. The mixture was cooled to 0° C., EDCI hydrochloride (0.38 mmol) and HOBT.NH3 (0.38 mmol) were added and stirring at rt was maintained overnight. Ethylacetate and water were added, the layers were separated, the aqueous layer was extracted with ethylacetate and the combined organic layers were washed with water and with 1N NaOH. They were then dried (Na2SO4), filtered and evaporated. Treatment with a small amount of methanol caused precipitation of the product, which was filtered affording the title compound. The amide was suspended in methanol and treated with 4M HCl in dioxane until pH was 1. Solvent was removed, the residue was treated with diethylether and the resulting solid was filtered, washed with diethylether and dried, affording the hydrochloric salt of the title compound (43% yield). ESI (+) MS: m/z 288 (MH+). 1H NMR: 7.36 (bd, J=39.63, 2H), 7.50-7.55 (m, 1H), 7.56-7.62 (m, 2H), 7.82-7.87 (m, 2H), 7.96 (d, J=8.78, 1H), 8.24 (d, J=8.78, 1H), 8.69 (d, J=6.34, 1H), 8.77 (d, J=6.34, 1H), 9.59 (s, 1H), 13.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]=2Cl)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>O1CCOCC1.C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([N+:21]([O-:23])=[O:22])[C:12]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-(3,4-dichlorophenyl)-2-chloro-3-nitro-5-trifluoromethylbenzamide (0.76 g; 1 eq.) in dioxane (12 ml) is added piperidine (0.4 ml; 2.2 eq.). After stirring for 18 hours at 25° C., 10 ml of water are added and the product is extracted with ethyl acetate. The organic phase is dried and concentrated. The orange oil obtained is dissolved in 2 ml of ethyl ether and 120 ml of hexane. After 3 days at 0° C., the solid is filtered off by suction and dried. 540 mg of N-(3,4-dichlorophenyl)-3-nitro-2-piperid-1-yl-5-trifluoromethylbenzamide are obtained (m.p.=144° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)(=[O:18])=[O:17])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:30]1[CH2:31][CH2:32][CH:27]([CH2:26][NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:16]([NH:15][C:6]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:18])[CH2:28][CH2:29]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCNCC2)ccc2c1CCCC2
Reaction time: 3 h

Procedure:
A solution of Example 557A (0.587 g, 1.1 mmol) in CH2Cl2 (10 mL) was treated with TFA (2 mL). The reaction was stirred for 3 hours, concentrated, and diluted with CH2Cl2. The organic layer was washed with pH 7 buffer solution, dried (MgSO4), filtered, and concentrated to provide the desired product. (MS (ESI(+)) m/e 458 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Mg]Br>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:7]1([OH:14])[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[NH:9][C:8]1=[O:13]
Reactant: CCOc1ccc2c(c1)C(=O)C(=O)N2
Reactant: Clc1ccccc1[Mg]Br
Product: CCOc1ccc2c(c1)C(O)(c1ccccc1Cl)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in Preparation 6 from 5-ethoxyisatin and 2-chlorophenylmagnesium bromide (prepared according to P. G. Gassman in J. Am. Chem. Soc., 1974, 9, 5512).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)c(Cl)c1
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1Cl

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [NH:1]([C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C=O)C.C(Cl)(Cl)Cl>[NH:1]([C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])=[C:10]([Cl:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc(Nc2ccccc2)nc2nc[nH]c12
Reactant: CC(=O)OCCCCBr
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCCn1cnc2c(Cl)nc(Nc3ccccc3)nc21
Yield: 45 %

Procedure:
Reaction between 2-anilino-6-chloropurine and 4-acetoxybutyl bromide was performed as described in A.a., above, giving 2-anilino-6-chloro-9-(4-acetoxybutyl) purine in a 45% yield (from DMF/chloroform), mp 195°-197° C. 1H NMR δ9.98 (s, 2-NH), 8.32 (s, 8-H), 7.31 (m, C6H5), 4.20 (t, 1'-CH2), 4.02 (t, 4'-CH2), 1.95 (s, CH3), 1.92, 1.58 (m, 2'/3'CH2).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17].[Hg](C#N)C#N>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(S)cc2)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(-c3ccc(C#N)cc3)cc2)SC[C@H]1OC(C)=O
Yield: 10.2 %

Procedure:
If the procedure described in Preparation I is followed starting from 2.3 g (10.9.10-3 mol) of 4-(4-mercaptophenyl)benzonitrile, 4.26 g (11.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.75 g (10.9.10-3 mol) of mercuric cyanide (Hg(CN)2), 0.540 g (yield: 10%) of the expected product is obtained after purification by flash chromatography using methylene chloride as the eluent.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>O.C(Cl)Cl>[C:12]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 82.4 %

Procedure:
Sodium hydroxide (7.6 g, 190 mmol) and 6-aminohexanoic acid (10 g, 76 mmol) were dissolved in distilled water (50 mL) at room temperature. Acryloyl chloride (8.24 g, 91 mmol) in dry CH2Cl2 (50 mL) was slowly added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 10 h. The reaction was quenched by adding 10% HCl (20 mL, pH 3) at room temperature and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated to give a product as a white solid (11.6 g, 82%). This compound was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([O+](CC)CC)[CH3:20]>ClCCl>[F:14][B-:15]([F:18])([F:17])[F:16].[CH2:19]([N:5]1[N:4]=[C:3]([S:2][CH3:1])[N+:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6]1)[CH3:20]
Reactant: CSc1nnnn1-c1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCn1nc(SC)[n+](-c2ccccc2)n1

Procedure:
A process which comprises reacting 5-methylthio-1-phenyltetrazole and triethyloxonium fluoroborate at a temperature of between about 15° and 40° C. in anhydrous dichloromethane to yield 3-ethyl-5-methylthio-1-phenyltetrazolium fluoroborate and isolating said fluoroborate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[N+:19]([C:22]1[C:23]([OH:32])=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([CH:29]=1)[CH:27]=O)([O-:21])=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:32][C:23]1[C:22]([N+:19]([O-:21])=[O:20])=[CH:29][C:26]([C@H:27]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)=[CH:25][C:24]=1[O:30][CH3:31]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (25.4 g,97.7 mmole), 5-nitrovanillin (16.73 g, 84.9 mmole), pyridinium para-toluenesulfonate (PPTS) (8.52 g, 33.9 mmole) and 100 ml dry benzene were refluxed under an argon atmosphere with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The reaction was cooled to room temperature and the precipitated PPTS removed by vacuum filtration. Hexane (100 ml) was added to the filtrate and the precipitate collected by vacuum filtration. The yellow solid was washed with cold water, followed by minimal cold methanol and finally cold diethyl ether to leave 28.62 g of a 1:1.3 cis/trans ratio of product. Six recrystallizations from ethyl acetate/hexane gives 4.3 g of pure trans diastereomer. An additional 2.4 g trans product can be obtained by repeating the above crystallization process from the material remaining in the mother liquors. Once 6.7 g of trans product was isolated,0.315 g of cis diastereomer was isolated by recrystallizing the combined mother liquors from above.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:12]=1[NH2:13]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][C:12]2[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:11]=2[F:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1cccc(F)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: COc1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methoxy-phenyl)-amine was prepared from 2,4,5-Trichloro-pyrimidine and 2-Fluoro-6-methoxyaniline in an analogous manner to Example 1230a. Title product was obtained as an off white solid (3.80 g, 62%). MP=133-135. LCMS 289.03 (M+H), HPLC purity=94%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 7.39-7.35 (m, 1H), 7.00-6.91 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)#[CH:25]>>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CC(C)(C)OC(=O)N1CCC(c2cnnn2C2CCc3c(CC(=O)O)c4ccccc4n3C2)CC1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and tert-butyl 4-ethynylpiperidine-1-carboxylate. MS (+ESI) m/z: 480.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.34 mmol, see step (b) Example 9) and 3-chlorophenylboronic acid (10 mg, 0.68 mmol). Yield 180 mg (95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br[Mg][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])[OH:12]
Reactant: COc1ccc(Cl)cc1[Mg]Br
Reactant: Cc1c(Cl)ccc2c1C(=O)C(=O)N2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(O)C(=O)Nc2ccc(Cl)c(C)c21
Reaction time: 3 h

Procedure:
1.96 g of 5-chloro-4-methyl-1H-indol-2,3-dione was added under ice cooling and a nitrogen atmosphere to a 50 mL tetrahydrofuran solution of 440 mg of sodium hydride, and the reaction mixture was stirred for 1 hour. After this, a previously prepared 15 mL tetrahydrofuran solution of bromo(5-chloro-2-methoxyphenyl)magnesium was added dropwise over a period of 10 minutes. The reaction mixture was stirred for 3 hours at the same temperature, after which 50 mL of a saturated ammonium chloride aqueous solution was added, and the reaction mixture was stirred for another 30 minutes at room temperature. After liquid separation, the aqueous layer was extracted with ethyl acetate (30 mL×3), and the combined organic layer was washed with saturated brine and dried with sodium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was stirred and washed with isopropyl ether, and the solids were then filtered off to obtain 2.43 g of the titled compound (yellow solid).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)CF
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)CF
Yield: 33 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1-fluoro-2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (70 mg, 33%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11](OC)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][OH:12]
Reactant: COC(=O)C1Cc2ccccc2N1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1c2ccccc2CC1CO
Yield: 100.3 %

Procedure:
A procedure similar to that described in Preparation 2 was repeated, except that 8.0 g of methyl 1-methylindoline-2-carboxylate (prepared as described in Preparation 5), 1.91 g of lithium aluminum hydride and 250 ml of tetrahydrofuran were used, to give 6.85 g of the title compound having Rf=0.35 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:24])=O.C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(CNC(=O)C2(C)CCCCC2)cc1C(=O)Cl

Procedure:
A mixture of 2-methyl-5-[(1-methylcyclohexylcarbonylamino)methyl]benzoic acid (0.250 g, 0.864 mmol), 0.16 mL thionyl chloride, 15 mL DCM and 10 μL DMF were heated at reflux for 2 h and concentrated. The crude acid chloride was used without further purification.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:14].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:14])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)ccc1N=C=S
Temperature: 25 °C
Reaction time: 28 h
Yield: 103 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 4-amino-3-methylbenzoic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0 mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 28 hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of 5 minutes at 0° C., followed by stirring at 0° C. for further 1.5 hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (6 mL) and water (1 mL) were added, and the organic layer was washed once with 1M hydrochloric acid (1 mL) and then concentrated under reduced pressure to dryness to obtain 4-isothiocyanato-3-methylbenzoic acid as a cream-colored solid (0.30 g, yield: 103%, HPLC purity: 88%, HPLC retention time: 4.0 min). LC-MS ES-192 (retention time: 4.3 min, condition 1).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.O>CS(C)=O>[N:11]1[N:10]=[CH:9][N:8]([NH:7][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([CH:22]=2)=[N:19][O:20][N:21]=3)[CH:12]=1
Reactant: Nn1cnnc1
Reactant: Fc1ccc2nonc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1cc2nonc2cc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
26.70 Grams of potassium tert-butoxide was dissolved in 100 ml of anhydrous dimethylsulfoxide and 20.00 g of 4-amino-4H-1,2,4-triazole was added thereto, followed by stirring for 2 hours at room temperature. Next, 50 ml of an anhydrous dimethylsulfoxide solution containing 11.00 g of 5-fluorobenzofurazane was added dropwise to the solution over a period of 20 minutes and then the mixture was stirred for 15 minutes. The reaction mixture was poured into 500 ml of water and 500 g of ice and then washed with 200 ml of ethyl acetate. The solution was then adjusted to have pH of 7.0 with 1N hydrochloric acid to give crystals. The crystals were collected by filtration, and the remaining mother liquid was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the crude crystals thus obtained were recrystallized from ethanol. These were combined with the previously obtained crystals to give 12.49 g of 5-[(4H-1,2,4-triazol-4-yl)amino]benzofurazane.