Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO.O.[C:44](#N)[CH3:45]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH2:44][CH3:45])[CH:34]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: COc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Solvent: O
Solvent: CO
Product: CCCOc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1

Procedure:
(1.25 g, 83%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-3-propoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.28 (s, 1H), 7.80-7.70 (m, 3H), 7.53-7.09 (m, 13H), 6.94-6.87 (m, 1H), 5.23 (d, J=8.0 Hz, 1H), 4.68 (d, J=6.0 Hz, 1H), 4.22-4.15 (m, 2H), 3.93 (t, J=6.7 Hz, 2H), 3.60 (d, J=5.3 Hz, 1H), 3.52 (d, J=7.0 Hz, 1H), 1.85-1.72 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); [α]20D −11.34° (4.25 mg/mL, MeOH). LCMS retention time=1.972 min., m/z=561 (M+H), 99.0% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:2][C:3](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COC1
Solvent: ClCCl
Product: CCOC(=O)C=C1COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of oxetan-3-one (500 mg, 6.938 mmol) in DCM (15.00 mL) at 0° C. was added ethyl 2-triphenylphosphoranylideneacetate (2.659 g, 7.632 mmol). The solution was allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was then filtered through a pad of silica (washing with 30% EtOAc:Petrol ether). and the solvent removed under reduced pressure to give ethyl 2-(oxetan-3-ylidene)acetate as a colourless viscous oil (815 mg, 79%).
Reaction SMILES: [SH:1][CH:2]([SH:17])[C:3]([SH:16])([SH:15])[C:4]([O:6][CH2:7][C:8]([CH2:13][OH:14])([CH2:11][OH:12])[CH2:9][OH:10])=[O:5].[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(N(CC)CC)C.C(#N)C>[C:21]([O:14][CH2:13][C:8]([CH2:11][OH:12])([CH2:9][O:10][C:21](=[O:22])[CH2:20][C:19]([CH3:18])=[O:23])[CH2:7][O:6][C:4](=[O:5])[C:3]([SH:15])([SH:16])[CH:2]([SH:1])[SH:17])(=[O:22])[CH2:20][C:19]([CH3:18])=[O:23]
Reactant: C=C1CC(=O)O1
Reactant: O=C(OCC(CO)(CO)CO)C(S)(S)C(S)S
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)CC(=O)OCC(CO)(COC(=O)CC(C)=O)COC(=O)C(S)(S)C(S)S
Temperature: 70 °C

Procedure:
To a solution of 20.0 g. (0.041 mol) of pentaerythritol tetramercaptopropionate in 20 g. of acetonitrile was added 7.9 g. (0.094 mol. 2.3 equiv.) of diketene. Upon addition of triethylamine catalyst (30 mg) an exotherm of 17° C. was observed. After 30 minutes the reaction mixture was warmed to 70° C. for an additional 30 minutes to ensure complete reaction. Solvent was removed on a rotary evaporator.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[N:14]=1.CO>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[NH2:20][C:15]1[N:14]=[C:13]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:18]=[C:17]([NH2:19])[N:16]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Oc2cc(N)nc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.2 %

Procedure:
Methyl 4-hydroxybenzoate (1.52 g, 10.0 mmol) was dissolved in 18 mL of anhydrous dioxane in 10-20 mL microwave vial (Personal Chemistry) and solid Cs2CO3 was added to this solution. The suspension was stirred at ambient temperature for 10 min, then 4-chloro-2,6-diaminopyrimidine (1.45 g, 10.0 mmol) was added. The vial was capped and microwaved at 200° C. for 40 min. Then MeOH was added to dissolve the formed suspension to produce a clear amber solution. The solution was transferred into a round-bottom flask and concentrated down to ca. 20 mL. This solution was purified by silica gel chromatography using 100% ethyl acetate as eluent. The product was additionally re-crystallized from ca. 50 mL of 4:1 mixture of EtOAc/MeOH. The product was filtered, washed with 40 mL of EtOAc, 40 mL of anhydrous Et2O and dried in vacuo to give the title product as a white solid (0.812 g). Yield 31.2%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][NH:22]3)=[CH:18][CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29][CH2:30]Br>CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[CH:21][N:22]3[CH2:30][CH2:29][O:28][CH3:27])=[CH:18][CH:17]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3cc[nH]c3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1ccc2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Reaction time: 2 h

Procedure:
To a round-bottomed flask was added, (2E)-3-[4-(tert-butyl)phenyl]-N-indol-6-ylprop-2-enamide, Example 189, (320 mg, 1.0 mmol) and anhydrous DMF (20 mL). The solution was stirred magnetically and treated with sodium hydride (0.10 g, 2.5 mmol, 60% dispersion in mineral oil, Aldrich) followed by 2-bromoethyl methyl ether (140 mg, 1.0 mmol, Aldrich). Stirring was continued at 25° C. for 2 h, then the reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc. The organic extract was concentrated in vacuo. Purification by silica gel chromatography (60:40 hexane:EtOAc) provided the title compound as a yellow solid. MP 133° C. MS (ESI, pos. ion) m/z: 377 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccc(F)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Yield: 112.7 %

Procedure:
5-Fluoropyridin-2-amine (500 mg, 4.46 mmol) and 2,4-dimethoxybenzaldehyde (674 mg, 4.06 mmol) were stirred in dichloromethane (10 mL) at room temperature for 30 minutes. Sodium triacetoxyborohydride (1.3 g, 6.08 mmol) was added portion wise. The mixture was then stirred at room temperature for 18 hours before treatment with 1M aqueous sodium hydroxide solution (10 mL). The aqueous layer was separated and extracted with dichloromethane (10 mL). The combined organic layers were dried through a phase separating cartridge and evaporated to afford the title compound (1.2 g) as a brown solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]1=[O:17])[CH2:7]2.[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C>[I:3][C:4]1[CH:5]=[C:6]2[C:19](=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH2:18][C@:8]1([C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[C:9]1=[O:17])[CH2:7]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc(I)c([N+](=O)[O-])cc1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(I)c([N+](=O)[O-])cc3C2)c2cccnc21
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 525 mg, 13.1 mmol) was added to a solution of (2R)-5-iodo-6-nitro-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (5.14 g, 12.6 mmol) in DMF (40 mL) at 0° C. and the mixture was stirred for 5 min. 2-(Trimethylsilyl)ethoxymethyl chloride (2.23 mL, 12.6 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with dilute aqueous NaHCO3 (200 mL) and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=538 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([CH2:24][CH3:25])=[C:31]([N+:32]([O-:34])=[O:33])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Product: CCc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]

Procedure:
The title compound was synthesized in a similar manner as described for for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-ethyl-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 208.1.2) to give the title compound as a yellow foam. (HPLC: tR 2.72 min (Method A); M+H=444 MS-ES).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:24])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:25][NH:26][CH2:27][CH2:28][C:3]1=2
Reactant: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)cn1
Yield: 29 %

Procedure:
tert-Butyl 5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (220 mg, 0.47 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (50.2 mg, 29%) as a yellow solid: mp 295-305° C.;
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:19])=[C:10]2[C:17]([CH3:18])=[N:16][S:15][C:11]2=[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCCCOC(=O)c1nc(Br)c2snc(C)c2c1O
Product: CCCCOC(=O)c1nc(-c2ccccn2)c2snc(C)c2c1O

Procedure:
The title compound was synthesized in analogy Example 3 from 7-bromo-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and 2-(tributylstannyl)pyridine: MS (m/z) 344.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 62.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (439 mg, 1.15 mmol, 62%) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl.ClCCl>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(6-Bromopyridin-3-yl)ethanone was dissolved in 50 mL of chloroform and cooled to 0° C., to which was added catalytic amount of AlCl3 and 2.65 mL of bromine in 25 mL of chloroform. The addition of bromine lasted 1 h to keep the reaction solution at 0° C. After stirring at 0° C. overnight, the mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford 2-bromo-1-(6-bromopyridin-3-yl)ethanone which was used in the next step with out further purification. LCMS: [M+1]+=279.
Reaction SMILES: C([N:8]([C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C@@H](C)C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:8][C@@H:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]
Reactant: [H][H]
Reactant: COC(=O)[C@@H](C)[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](C)[C@@H](N)c1ccccc1

Procedure:
A mixture of methyl (2S,3R,αS)-3-(N-benzyl-N-a-methylbenzylamino)-2-methyl-3-phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium-on-carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a balloon of hydrogen for 24 h. The catalyst was removed by filtration followed by evaporation and co-distillation with toluene to provide the title compound as a white solid. MS (m/z): 194.2 (M+H)+; C11H15NO2 requir. 193.3.
Reaction SMILES: COC(=O)CC(C1C=CC(C(F)(F)F)=CC=1)[CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[NH:13])[NH:7]1.F[C:26](F)(F)[C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=1.[ClH:41]>>[ClH:41].[NH:13]=[C:8]1[CH:9]([CH:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:10][CH2:11][CH2:12][CH2:6][NH:7]1
Reactant: COC(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(c1ccc(C(F)(F)F)cc1)C1CCCCC(=N)N1
Agent: Cl
Product: COC(=O)CC(c1ccc(C)cc1)C1CCCCNC1=N

Procedure:
methyl 3-[4-(trifluoromethyl)phenyl]propenoate methyl hexahydro-7-imino-b-(4-(trifluoromethyl)phenyl]-1H-azepine-2-propanoate, monohydrochloride;
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22](I)=[C:21]([CH3:26])[CH:20]=2)[CH:15]=[CH:16][C:17]=1[I:18].C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[CH3:26][C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][C:17]([I:18])=[C:12]([CH3:11])[CH:13]=2)[CH:24]=[CH:23][C:22]=1[N:4]([C:1](=[O:3])[CH3:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(-c2ccc(I)c(C)c2)ccc1I
Reactant: CC(=O)Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N(c1ccccc1)c1ccc(-c2ccc(I)c(C)c2)cc1C
Yield: 69.3 %

Procedure:
16.2 g (0.12 mol) of acetanilide, 56.4 g (0.13 mol) of 3,3'-dimethyl-4,4'-diiodobiphenyl, 18.0 g (0.13 mol) of anhydrous potassium carbonate, 1.71 g (0.027 mol) of copper powder, and 30 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 192° C. to 203° C. for 13 hours. The reaction product was then extracted with 160 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 7/1 mixture of toluene and ethyl acetate) to obtain 36.7 g (yield: 69.3%) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)acetanilide. Subsequently, 13.2 g (0.030 mol) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)acetanilide thus obtained, 6.09 g (0.036 mol) of diphenylamine, 5.11 g (0.037 mol) of anhydrous potassium carbonate, 0.44 g (0.007 mol) of copper powder, and 10 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 198° to 211° C. for 13 hours. The reaction product was then extracted with 100 ml of toluene. The insoluble contents were then removed by filtration. The filtrate was then concentrated to obtain an oily matter. The oily matter thus obtained was then dissolved in 50 ml of isoamyl alcohol. The material was then hydrolyzed with 1 ml of water and 2.38 g (0.036 mol) of 85% potassium hydroxide at a temperature of 130° C. The reaction solution was then subjected to steam distillation to distill off isoamyl alcohol. The residue was extracted with 200 ml of toluene, washed with water, and then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 1/3 mixture of toluene and n-hexane) to obtain 9.27 g (yield: 70.1%) of 3,3'-dimethyl-N,N,N'-triphenylbenzidine. The melting point of the product was from 104.0° C. to 105.0° C.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)[CH2:12][CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)=[O:33]
Reactant: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCCC3)cn1
Reactant: O=C(O)C(=O)c1ccccc1
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)nc1)c1ccc2c(c1)CCCC2)c1ccccc1
Yield: 100.6 %

Procedure:
In analogy to example 7, step 1, (5,6,7,8-tetrahydro-naphthalen-2-yl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (250 mg, 0.78 mmol, prepared as described in example 9, step 1) and benzoylformic acid (141 mg, 0.939 mmol) were coupled to provide the title compound (355 mg, 100%) as a yellow oil which was used without further purification in the next step.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6]([OH:14])([CH2:7]3)[CH2:5]1)[CH2:11]2.I[CH3:16]>O1CCCC1.C(Cl)Cl>[CH3:16][O:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([NH2:3])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC12CC3CC(CC(N)(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred, ice-water chilled suspension of potassium hydride (0.680 gm; 5.95 mmol) in 15.0 ml of tetrahydrofuran is added a mixture of 1-aminoadamantane-3-ol (1.00 g; 5.95 mmol) and 15.0 ml of tetrahydrofuran dropwise over 30 minutes. The resulting mixture is then stirred for an addition 30 minutes and iodomethane (0.370 ml; 5.95 mmol) is then added dropwise over one minute. The resulting opaque white reaction is then stirred at room temperature for 18 hours. The mixture is then diluted with 50 ml of methylene chloride and filtered to remove the inorganic impurities. The filtrate is then concentrated and purified on silica gel employing a SIMS/Biotage apparatus and 19% methanol and 1% ammonium hydroxide in methylene chloride as eluent to yield 3-methoxy-1-adamantylamine as an opaque oil.
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=N.C(O)(=O)C>O>[NH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=N)N1CCC(c2n[nH]c3ccccc23)CC1
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 46.4 %

Procedure:
A solution of 4.7 g of 4-(1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester and 80% of acetic acid was heated under reflux for 48 hrs. The reaction mixture was cooled and poured into water The aqueous phase was extracted with ether and then made basic by the slow addition of a 50% aqueous sodium hydroxide solution. A solid separated from the solution. The solid was collected and dried. Recrystallization from ethanol yielded 1.7 g (46%) of product. Concentration of the mother liquors from this and another experiment gave additional product mp 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12](N1C=CN=C1)=[O:13]>O1CCCC1.CCOCC>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:12]([O:11][CH3:10])=[O:13])[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: COC(=O)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)Nc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
46.3 g (0.32 mol) of 6-chloro-2,4-diamino-pyrimidine are dissolved in 1000 ml of tetrahydrofuran and treated with 57.9 g (0.517 mol) of potassium tert.butylate. The gel-like precipitate is stirred at room temperature for 1 hour. A solution of 60.5 g (0.48 mol) of 1-methoxycarbonylimidazole in 100 ml of ether is added thereto at a temperature of 10° within 90 minutes. The mixture is thereafter stirred at 25° for a further 2 hours, the solvent is then evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The organic solution is washed with cold water and dried over sodium sulfate. After evaporation of the solvent under reduced pressure, the residue is crystallized from acetone/ether. After recrystallization from chloroform/methanol/hexane, there is obtained methyl 2-amino-6-chloro-4-pyrimidinecarbamate of melting point 225°-226°.