Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.C([Al]CC(C)C)C(C)C.CC(O)=O>C1(C)C=CC=CC=1>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][OH:2])=[CH:15][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: OCCCCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Yield: 64.8 %

Procedure:
To a solution of 4-[(S)-2-(4-benzyl-phenoxymethyl)-pyrrolidin-1-yl]-butyric acid methyl ester (0.37 g, 1 mmol) in toluene (2 mL) was added 1.5M diisobutylaluminum hrdride in toluene (2 mL, 3 mmol) at −60° C. and then stirred the reaction at −30 to −20° C. for 2 h, followed by addition of 15% AcOH dropwise. The reaction was stirred at room temperature for 30 minutes and formed white solid was filtered and washed with acetone. The filtrate was concentrated in vacuo to yield the title compound as a white solid (0.22 g, 79%); MS; m/z 340.8 (M+H). 1H NMR (400 HMz, CDCl3) δ 1.61-2.26 (m, 8H), 2.79 (m, 1H), 2.85 (m, 1H), 3.25 (m, 2H), 3.42 (m, 2H), 3.54 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 3.92 (s, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.09-7.21 (m, 5H), 7.28 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[S:7])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([NH2:20])=[O:19])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[S:7][CH:12]([C:14]3[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=3[O:16][CH2:17][C:18]([NH2:20])=[O:19])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)COc1ccccc1C=O
Reactant: NNC(=S)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)COc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Reaction time: 0.17 h

Procedure:
To a heterogeneous mixture of 4-chloro-thiobenzoic acid hydrazide (1.3 mmol) in 12 mL of CH2Cl2 is added 2-(2-formylphenoxy)acetamide (1.53 mmol) and DIEA (1.53 mmol). After 10 minutes the mixture become homogenous and the reaction is complete by TLC and LCMS to give 2-(2-(5-(4-chlorophenyl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)phenoxy)-acetamide which is used as such in the next step without evaporation of the solvent.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][C:9](=O)[C:8]=2[C:22]2[NH:26][N:25]=[N:24][N:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:29])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:29][C:9]1[C:8]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:19])([F:18])[F:20])[CH:15]=2)[N:10]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(-c2ccccc2)c1-c1nnn[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 70 °C
Yield: 63.6 %

Procedure:
4-Phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-1H-quinolin-2-one (160 mg, 448 μmol) was twice co-evaporated with toluene (5 ml). Then toluene (5 ml), phosphorus oxychloride (446 mg, 271 μl, 2.91 mmol) and N,N-diisopropylethylamine (72.3 mg, 97.8 μl, 560 μmol) were added and the mixture was heated to 70° C. for 5 h. Then all volatiles were removed and toluene (5 ml) was added and evaporated twice. Then ethanol (5 ml) was added and evaporated. Water and methanol were added to the remaining residue and the solid was filtered off and dried to obtain the title compound (107 mg, 64%) as brown solid. MS (ESI): 374.3 (M−H)−.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH2:39])([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>C(#N)C>[C:26]([O:30][C:31](=[O:42])[C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:41])[C@H:38]([CH3:40])[NH:39][C@@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 13.1 %

Procedure:
A solution of ethyl 2-bromo-9-phthalimidononanoate [prepared according to Chem. Pharm. Bull. 34, 2078 (1986)] (3 g), L-alanyl-L-proline tertiary butylester (1 g) and triethylamine (0.8 ml) in acetonitrile (200 ml) is subjected to 60 hours' reflux. Acetonitrile is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate. The solution is dehydrated with anhydrous sodium sulfate, and thereafter is concentrated to obtain an oily residue. When this substance is applied to a silica gel chromatography (ethyl acetate:n-hexane=3:1) for separative purification, 310 mg of N-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]-L-alanyl-L-proline tertiary butylester is obtained as a colorless oil from the first effluence.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.C[O:13][C:14](=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)=[CH:17][CH:16]=1>>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:21]([CH:31]1[CH2:32][CH2:33][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=2[CH3:11])=[O:10])[CH2:35][CH2:36]1)[C:18]1[CH:17]=[CH:16][C:15]([C:14]([OH:42])=[O:13])=[CH:20][CH:19]=1)#[N:30]
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with 4,6-dimethyl-pyrimidine-5-carboxylic acid (71 mg, 0.46 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester gave 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a brown solid (105 mg, 64% over 2 steps).
Reaction SMILES: [Na].CN([SiH3])[Si](C)(C)C.O1C[CH2:12][CH2:11][CH2:10]1.O1CCCC1.[CH:19]1([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20]1.C(Br)C=C>O>[CH:19]1([CH:23]([CH2:12][CH:11]=[CH2:10])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CC1CCC1
Reactant: C1CCOC1
Agent: CN([SiH3])[Si](C)(C)C
Agent: [Na]
Solvent: C=CCBr
Solvent: O
Product: C=CCC(C(=O)OCC)C1CCC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 1.9 M tetramethyldisilazane sodium-tetrahydrofuran solution (9.44 mL, 18.0 mmol) was added dropwise over 10 minutes to a tetrahydrofuran (40 mL) solution of ethyl 2-cyclobutylacetate (2.32 g, 16.3 mmol) cooled to −78° C., and the mixture was then stirred at −78° C. for 10 minutes. Subsequently, a tetrahydrofuran (10 mL) solution of allyl bromide (7.90 g, 65.3 mmol) was added dropwise thereto over 10 minutes, and the mixture was stirred at room temperature for 17 hours. The mixture was treated with water, and volatile portions were then removed under reduced pressure. To the obtained liquid, ethyl acetate and water were added, and the obtained organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a yellow oil substance (1.80 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.[OH-].[Na+].O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Yield: 83.4 %

Procedure:
To a solution of ethyl(1RS,2SR,3SR)-1-(4-methoxyphenyl)-3-phenylindane-2-carboxylate, (5.5 g, 14.8 mmol) in EtOH (70 ml) was added SM NaOH (9 ml, 45 mmol). The resulting mixture was stirred under an argon atmosphere for 1 d, at which time H2O (70 ml) was added. The mixture was concentrated under reduced pressure. The aqueous residue was extracted with Et2O, and the Et2O extracts were discarded. The aqueous phase was acidified with 6M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide an oily residue which crystallized upon standing. The solid material was recrystallized from EtOAc/hexanes to afford the title compound (4.25 g, 83%); m.p. 164°-166° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[C:18]([O-])([O-])=O.[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C.O>C(Cl)Cl>[CH2:11]([O:10][C:8]([N:4]1[CH2:3][C:2]([O:1][CH3:18])=[N:7][CH2:6][CH2:5]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC1=NCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of benzyl 3-oxopiperazine-1-carboxylate (20.50 g, 10.67 mmol) in CH2Cl2 (100 ml) was cooled to 0° C. and treated with Na2CO3 (23.0 g, 217 mmol) for 10 minutes. Neat trimethyloxonium tetrafluoroborate (5.50 g, 37.2 mmol) was added in one portion, then the reaction is allowed to warm to room temperature for 6 hours. The reaction was poured into water (100 ml), and the layers were separated. The aqueous layer was re-extracted aqueous with 50 ml CH2Cl2 and the combined organic layers were washed with brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5-methoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid benzyl ester (2.51 g, 95%) as an oil. LCMS (Table 1, Method a) Rt=3.00 min, m/z 249.24 (M+H)+−; 1H NMR (400 MHz, DMSO-d6) δ 7.36 (m, 5H), 5.16 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.47 (m, 2H)
Reaction SMILES: C(N1CCC(OC2C=CC3N4CCCNC(=O)C4=CC=3C=2)CC1)(C)C.[CH3:26][O:27][C:28]([C:30]1[N:46](C(OC(C)(C)C)=O)[C:33]2=[N:34][CH:35]=[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[C:32]2[CH:31]=1)=[O:29].[C:54]([O:58][C:59]([N:61]1[CH2:65][CH2:64]OS1(=O)=O)=[O:60])([CH3:57])([CH3:56])[CH3:55].CC(C)([O-])C.[K+]>>[CH3:26][O:27][C:28]([C:30]1[N:46]([CH2:64][CH2:65][NH:61][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:60])[C:33]2=[N:34][CH:35]=[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:37]=[C:32]2[CH:31]=1)=[O:29]
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Agent: [K+]
Product: COC(=O)c1cc2cc(OCc3ccccc3)cnc2n1CCNC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate M), 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/072584) and potassium tert-butoxide, to give the product as a colorless foam (89%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH3:34]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[C:27]([CH3:34])[CH:28]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: Cc1cc(CBr)ccc1F
Product: Cc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)ccc1F
Yield: 0.9 %

Procedure:
The title compound (0.001 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14. found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.43 (m, 4H), 7.08-7.06 (m, 1H), 6.99-6.97 (m, 2H), 5.32 (s, 2H), 3.88 (s, 2H), 3.16-3.14 (m, 2H), 2.89-2.86 (m, 2H), 2.22 (d, J=1.6 Hz, 3H), 1.80 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[CH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)C(=O)CC(Sc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a mixture of 4-chlorobenzalpinacolone (22.3 g), triethylamine (5 drops) and ethanol (250 ml) was added thiophenol (12 g) and the mixture was kept to 70° C. for 4 hours. After ice-cooling, the resulted precipitates were collected by filtration, washed with cold ethanol and dried to give white crystals of the captioned compound (29 g; 84%). m.p. 127°-128° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Br[C:13]#[N:14]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13]([NH2:14])=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: N#CBr
Solvent: O
Solvent: CCO
Product: Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
7.6 g (50 mmol) of 4-nitro-ortho-phenylenediamine was dissolved were dissolved in 100 mL of ethanol and 20 mL of H2O. 7.9 g (75 mmol) of BrCN was added in one portion to this stirring solution, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 20 mL then neutralized with saturated NaHCO3 solution to pH 8, and resulting solid 5-nitro-1H-benzoimidazol-2-ylamine collected via filtration was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](=S)=[S:20].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[CH:1]1([N:11]=[C:19]=[S:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCc2ccccc21
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: S=C=NC1CCCc2ccccc21
Reaction time: 1 h

Procedure:
To a stirred solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthylamine in ethyl acetate is added 0.01 mole of triethylamine and 0.011 mole of carbon disulfide. The mixture is stirred about one hour and then 0.01 mole of dicyclohexyl carbodiimide is added. The mixture is stirred overnight, and the mixture filtered to remove solid dicyclohexylthiourea. The filtrate is evaporated, and the residue is purified by dry column chromatography to give 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH:13]([NH:15][CH2:16][CH2:17][C:18](=O)[CH3:19])=[O:14].B(F)(F)F>C1C=CC=CC=1>[CH3:19][C:18]1([CH2:17][CH2:16][NH:15][CH:13]=[O:14])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: CC(=O)CCNC=O
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: c1ccccc1
Product: CC1(CCNC=O)OCCC2=C1Cc1ccccc12

Procedure:
A mixture of indene-3-ethanol (1.6 g), 4-(formylamino)-2-butanone (1.2 g), described by H. Bredereck, et al., Chem. Ber., 2423 (1960), benzene (40 ml) and boron-trifluoride etherate (3 ml) is stirred at reflux temperature for 3 hr. The reaction mixture is washed with saturated sodium bicarbonate solution, dried and evaporated to dryness to afford the N-formyl derivative, 1-methyl-1-[2-(formylamino)ethyl]-1,3,4,9-tetrahydroindeno[2,1-c]pyran, nmr (CDCl)3 δ 3.3 (m, 4H), 6.5 (broad, 1H), 7.25 (m, 4H), 8.08 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20](O)[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:19]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1ccnc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(OCc2c(-c3ccccc3)noc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.5 g, 8.0 mmol) in THF (79 mL) was added 2-hydroxy-isonicotinic acid methyl ester (1.8 g, 12.0 mmol) and triphenylphosphine (2.8 g, 11 mmol) at room temperature under an argon atmosphere. Then diethyl azodicarboxylate (1.64 mL, 11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Then 2-hydroxy-isonicotinic acid methyl ester (0.2 g, 0.17 mmol) was added and the resulting mixture stirred at room temperature for 1 h and then heated at 60° C. for 1 h. After cooling to room temperature, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (0.99 g, 38%) as a light yellow solid. MS: m/e=325.1 [M+H]+.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][O:14][C:15]1[C:16]([N+:22]([O-:24])=[O:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:13][O:14][C:15]1[C:16]([N+:22]([O-:24])=[O:23])=[N:17][C:18]([CH2:21][Br:25])=[CH:19][CH:20]=1
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A catalytic amount of α,α'-azobis(isobutyronitrile) was added to 3-methoxy-6-methyl-2-nitropyridine (described in Acta Chem. Scand., vol. 23, pages 1791-1796) (7.1 g), N-bromosuccinimide (7.1 g) and carbon tetrachloride (80 ml), and the mixture was refluxed for 16 hours. After the reaction, while the reaction mixture was still hot, it was suction-filtered to separate the insoluble succinimide. The filtrate was cooled to room temperature whereupon the unreacted 3-methoxy-6-methyl-2-nitropyridine precipitated as crystals. The crystals were separated by filtration. The residue was concentrated and then vacuum distilled to give 3-methoxy-2-nitro-6-pyridylmethyl bromide (2.1 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5](=[C:7]([C:16]([O:18][CH3:19])=[O:17])[S:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.[CH2:20](I)[CH3:21].[OH-].[Na+]>CO>[CH2:20]([S:1][C:2]1[NH:3][C:4]2[C:5](=[C:7]([C:16]([O:18][CH3:19])=[O:17])[S:8][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH3:21]
Reactant: CCI
Reactant: COC(=O)c1sc(-c2ccccc2)c2[nH]c(S)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1nc2c(C(=O)OC)sc(-c3ccccc3)c2[nH]1
Yield: 68 %

Procedure:
A solution of methyl 2-mercapto-4-phenylthieno[3,4-d]imidazole-6-carboxylate (1.7 g), ethyl iodide and 2N NaOH (3 ml) in methanol (30 ml) was stirred at room temperature for 6.5 hr. The reaction solution was concentrated to dryness and the residue was triturated with H2O to give a crystalline product. Recrystallization from MeOH-EtoAc to give pale yellow needles (1.3 g, 68%). m.p. 214°-215° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[CH3:47][C:48]1[O:52][N:51]=[C:50]([C:53](Cl)=[O:54])[CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:53]([C:50]2[CH:49]=[C:48]([CH3:47])[O:52][N:51]=2)=[O:54])[CH2:41]1)=[O:39]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)C2)no1
Yield: 62 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 62% yield. LCMS for C29H29ClN7O3 (M+H)+: m/z=558.2.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[N:15]=[C:14]([NH:16][CH:17]=[O:18])[N:13]=[C:12]([Cl:19])[C:11]=1[NH:20][CH:21]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(OCC)OCC)(=O)C>[CH2:1]([O:8][N:9]1[CH:21]=[N:20][C:11]2[C:10]1=[N:15][C:14]([NH:16][CH:17]=[O:18])=[N:13][C:12]=2[Cl:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(NOCc2ccccc2)n1
Agent: CCOC(OCC)OC(C)=O
Product: O=CNc1nc(Cl)c2ncn(OCc3ccccc3)c2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
6-Benzyloxyamino-4-chloro-2,5-diformamidopyrimidine (1.2 g, 3.73 mmol) and diethoxymethyl acetate (20 ml) was stirred at 120° C. for 2.5 hours, cooled and evaporated under reduced pressure. A solution of the residue in methanol (20 ml) and 0.880 ammonia (2 ml) was stirred at 20° C. for 1 hour, the solvent removed under reduced pressure and the residue co-evaporated with methanol. Column chromatography on silica gel (eluted with chloroform-ethanol, 100:1) afforded the title compound (700 mg, 62%). IR: νmax (KBr) 3119, 1702, 1611, 1577, 1505, 1440 cm-1 ; 1H NMR: δH [(CD3)2SO], 5.44 (2H, s, CH2Ph), 7.45 (5H, m, Ph), 8.54 (1H, s, H-8), 9.34 (1H, s, CHO), 11.30 (1H, br.s, D2O exchangeable, NH). Found: C, 49.99; H, 3.37; N, 22.43%, m/z 303.0523. C13H10N5O2Cl+0.5 H2O requires: C, 49.92; H, 3.55; N, 22.40%, m/z 303.0520.