Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)([O:4][CH2:5][CH3:6])[CH2:2][CH3:3].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>>[CH2:5]([O:4][C:1](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH2:2][CH3:3])[CH3:6]
Reactant: CCOC(CC)(OCC)OCC
Reactant: N#CCC#N
Product: CCOC(CC)=C(C#N)C#N
Reaction time: 8 h

Procedure:
Heat a mixture of triethyl orthopropionate (446 g, 2.53 mol) and malononitrile (163.9 g, 2.48 mol) at reflux under nitrogen for 1.5 h. Cool the mixture and stir overnight. Distill the dark mixture under vacuum (10-15 torr, 135-142° C.) to afford the title compound as a pale yellow oil: 1H NMR (CDCl3) δ 4.40 (q, J=7.0, 2H), 2.63, (q, J=7.7, 2H), 1.41 (t, J=7, 3H), 1.23 (t, J=7.7, 3H); 13C NMR (CDCl3) 189.7, 113.3, 111.8, 68.3, 64.1, 25.5, 14.6, 11.3.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:53])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N:34]3[CH2:38][C@H:37]([CH2:39][N:40]4C(=O)C5C(=CC=CC=5)C4=O)[O:36][C:35]3=[O:51])=[CH:29][C:28]=2[CH3:52])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.O.ClCCl>C(O)C>[NH2:40][CH2:39][C@@H:37]1[O:36][C:35](=[O:51])[N:34]([C:30]2[CH:29]=[C:28]([CH3:52])[C:27]([N:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:22]3=[O:53])=[C:32]([CH3:33])[CH:31]=2)[CH2:38]1
Reactant: Cc1cc(N2C[C@H](CN3C(=O)c4ccccc4C3=O)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: CN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N2C[C@H](CN)OC2=O)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 52.5 °C

Procedure:
130 g (179 mmol) of the compound from Example 67A are dissolved in 650 ml of ethanol, 193 ml (2.68 mol) of a 40% strength aqueous methanamine solution are added and the mixture is heated at 50-55° C. for one hour. After cooling to room temperature, water and dichloromethane are added, the phases are separated and the organic phase is dried over sodium sulphate. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue (117 g, 89% of theory) is reacted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[Cl:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: Oc1cccc(Cl)c1
Reactant: OC1CCNc2ncc(Br)cc21
Solvent: ClCCl
Solvent: CO
Product: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Yield: 60 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (225 mg) was reacted with 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic alumina chromatography using a gradient of 0-1% methanol/methylene chloride as the eluting solvent gave the title compound as a white film (60% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.21 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 5.04 (s, 1H), 5.27 (t, J=3.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.00 (m, 2H), 7.24 (m, 1H), 7.48 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Fc1cccc(-c2cc(CCl)ccn2)c1
Product: COc1ccc(N(Cc2ccnc(-c3cccc(F)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (153 mg) and 4-chloromethyl-2-(3-fluorophenyl)pyridine (111 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[O:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)C=1C(O)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:11]([C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:5]=1[C:6]([Cl:8])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1c(Oc2ccccc2)cccc1Oc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1c(Oc2ccccc2)cccc1Oc1ccccc1

Procedure:
Fifteen parts of thionyl chloride or oxalyl chloride are added to 2 parts of 2,6-diphenoxybenzoic acid. The mixture is heated under reflux for 30 minutes, and the excess chloride is distilled. The residue crystallizes to give 2,6-diphenoxybenzoyl chloride, M.P. 72°-73°.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Br[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28][CH2:27]2
Reactant: Sc1ccccn1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCCCCSc3ccccn3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
14.4 gm (0.13 mol) of 2-mercapto-pyridine and 17.9 gm (0.13 mol) of potassium carbonate were stirred into 360 ml of dimethylsulfoxide which had been dried over a molecular sieve, and the solution was admixed with 36 gm (0.12 mol) of 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril (m.p. 142°-147° C.; prepared from 6-hydroxy-carbostyril and 1,4-dibromo-butane). The mixture was stirred for 15 hours at about 25° C., then poured into 3.6 liters of water, and the aqueous mixture was stirred for 30 minutes. The precipitate formed thereby was collected by suction filtration, thoroughly washed with water, dried and recrystallized from xylene in the presence of activated charcoal, yielding 32 gm (81.2% of theory) of a light yellow crystalline product having a melting point of 123°-124.5° C. It was identified to be the compound of the formula ##STR9##
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH2:25]O)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O=S(Cl)Cl>[C:15]1([CH3:27])[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH2:25][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: Cc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Yield: 99.5 %

Procedure:
A heterogeneous mixture of 3-chlorosulfonyl-4-methylbenzoic acid (11.7 g, 50.0 mmol) in 18 mL of SOCl2 was refluxed for 3 h. After the excess of SOCl2 was removed, the residual brown oil was dissolved in 50 mL of CH3CN, and then 2-(p-tolylsulfonyl)ethanol (9.4 g, 47.0 mmol, 0.95 eq.) was added. The mixture was heated to reflux temperature for 24 h. Thereafter most of CH3CN was removed, the resulting oil was purified by short column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give a light brown oil, which solidified on standing. The solid was dried further under vacuum to yield 19.5 g (99%) of 3-chlorosulfonyl-4-methylbenzoic acid 2-(p-tolylsulfonyl)ethyl ester (Intermediate 49).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1N
Yield: 74 %

Procedure:
A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 ml) containing conc. sulfuric acid (5.5 ml) was heated for 19 hours under reflux. The solvent was distilled off, and the residue was dissolved in water. The solution was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and concentrated to afford a pale brown oil (8.1 g, 74%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][C:13](/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:25])[C:8]=2[N:26]=1)[CH2:2][CH2:3][CH3:4]>[Pd]>[CH2:1]([C:5]1[N:6]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:25])[C:8]=2[N:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3cc(/C=C/c4ccccc4)ccc3c2n1CC(C)C
Agent: [Pd]
Product: CCCCc1nc2c(N)nc3cc(CCc4ccccc4)ccc3c2n1CC(C)C
Yield: 26.6 %

Procedure:
2-Butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine (562 mg, 1.41 mmol) was hydrogenated in a Parr bottle over palladium on carbon (10%) until the starting material was consumed as judged by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) analyses. Purification on silica (5% to 10% methanol in CH2Cl2 gradient) followed by recrystallization from boiling CH3CN afforded 150 mg of 2-butyl-1-isobutyl-7-phenethyl-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 181-182° C.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:17][O:18]/[N:19]=[C:20]1\[CH2:21][CH2:22][C:23]2[C:28]\1=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=2.C(N(CC)CC)C>COCCOC.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:2]3[C:3]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[N:4][N:5]4[CH:10]=[CH:9][CH:8]=[N:7][C:6]=34)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: CO/N=C1\CCc2cc(B(O)O)ccc21
Reactant: Brc1c(-c2ccncc2)nn2cccnc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CON=C1CCc2cc(-c3c(-c4ccncc4)nn4cccnc34)ccc21
Temperature: 60 °C
Yield: 48.5 %

Procedure:
To 3-bromo-2-(pyridin-4-yl)pyrazolo[1.5-a]pyrimidine (0.150 g; Example 7, step 4) and (E)-1-(methoxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (0.224 g; Example 1, Step 5) in 5.5 mL 1,2-dimethoxyethane, was added 0.167 mL triethylamine and 27 mg 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride catalyst. The mixture was heated at 60° C. for 16 hours, diluted with ethyl acetate, and washed with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to yield 94 mg (49% yield) product as a yellow solid. 1H NMR (CDCl3) was consistent with the desired structure. MS showed a M+1 molecular ion of m/z 356.2 by positive APCI.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[C@@:52]2([CH3:53])[C@@:15]([CH3:54])([C@@H:16]3[C:49](=[CH:50][CH2:51]2)[C@@:20]24[CH2:27][C@@H:26]([O:28][CH3:29])[C@H:25]([O:30][CH2:31][C@@:32]([CH3:47])([NH:36]S(C5C=CC(C)=CC=5)(=O)=O)[CH:33]([CH3:35])[CH3:34])[C@@:24]([CH3:48])([C@@H:19]2[CH2:18][CH2:17]3)[CH2:23][O:22][CH2:21]4)[CH2:14][CH2:13][C@@:12]1([C@H:56]([CH3:60])[CH:57]([CH3:59])[CH3:58])[CH3:55])=[O:10])C1C=CC=CC=1.N.CCOC(C)=O.[Na]>C(COC)OC.C(Cl)Cl.CO>[NH2:36][C@@:32]([CH3:47])([CH:33]([CH3:35])[CH3:34])[CH2:31][O:30][C@@H:25]1[C@@:24]2([CH3:48])[C@@H:19]3[CH2:18][CH2:17][C@H:16]4[C:49]([C@@:20]3([CH2:21][O:22][CH2:23]2)[CH2:27][C@H:26]1[O:28][CH3:29])=[CH:50][CH2:51][C@:52]1([CH3:53])[C@:15]4([CH3:54])[CH2:14][CH2:13][C@@:12]([C@H:56]([CH3:60])[CH:57]([CH3:59])[CH3:58])([CH3:55])[C@H:11]1[C:9]([OH:10])=[O:8]
Reactant: CO[C@@H]1C[C@@]23COC[C@](C)([C@@H]2CC[C@H]2C3=CC[C@@]3(C)[C@H](C(=O)OCc4ccccc4)[C@@](C)([C@H](C)C(C)C)CC[C@]23C)[C@H]1OC[C@@](C)(NS(=O)(=O)c1ccc(C)cc1)C(C)C
Agent: N
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1C[C@@]23COC[C@](C)([C@@H]2CC[C@H]2C3=CC[C@@]3(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]23C)[C@H]1OC[C@@](C)(N)C(C)C
Temperature: -35 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
A solution of Intermediate 5 (18.21 g, 21.60 mmol) in dimethoxyethane (300 mL) was added over about 20 minutes to liquid ammonia (approx. 400 mL) kept at −35 to −50° C. (bath temp). Sodium metal (4.0 g, in 0.2 g portions that were quickly washed with heptane prior to addition) was added to the ammonia solution over a period of 30 minutes ensuring that the reaction temperature was maintained at about −35° C. (bath temp). The deep blue reaction mixture was allowed to stir for 3 h. Analysis by TLC (50% EtOAc in Heptanes and 10% MeOH in DCM) indicated an incomplete reaction so additional sodium metal (1.0 g, divided into 0.5 g portions) was added over the course of about 10 minutes as described above. The reaction was stirred for an additional 2 h, whereupon the reaction was judged to be complete by TLC and LC-MS analysis. The reaction was quenched by the careful addition of isopropanol (10 mL, added dropwise over about 15 minutes), followed by 1:1 isopropanol-MeOH (80 mL over 30 minutes), and MeOH (40 mL over 30 minutes). The reaction mixture was stirred for 1 h and water (15 mL) was then added over 15 minutes. The ammonia was allowed to evaporate (several hours or overnight) and then water (300 mL) was added to the reaction. The mixture was extracted with EtOAc (3×350 mL). The organic solution was dried over anhydrous MgSO4. Removal of the drying agent and evaporation of the solvent gave a white solid (7.96 g). The aqueous solution was treated with brine (400 mL) and re-extracted with dichloromethane (3×300 mL). The combined dichloromethane extracts were dried (MgSO4), filtered and evaporated to afford additional white solid (4.53 g). The combined yield of Intermediate 7 was 12.49 g, which was used directly in the next step.
Reaction SMILES: [CH:1]([N:5]1[C:9]2[CH:10]=[C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]3=[O:26])[C:12]([F:14])=[CH:13][C:8]=2[S:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([N:5]1[C:9]2[CH:10]=[C:11]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:30])[C:16]3=[O:26])[C:12]([F:14])=[CH:13][C:8]=2[S:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCC(C)n1c(=O)sc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 48.3 %

Procedure:
To a solution of 1-[3-sec-butyl-6-fluoro-2 (3H)benzothiazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), methyl iodide (0.5 g) and potassium carbonate (1.6 g) were added, and the resultant mixture was heated at 40° to 80° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, and the precipitated crystals were collected by filtraction, washed and dried. The residue was purified by column chromatography to give 1-[3-sec-butyl-6-fluoro-2(3H) -benzothiazolon-5-yl]-3-metyl -4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (1.0 g ).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(-n2cnnn2)c1
Product: Cc1cc(-n2cnnn2)ccc1[N+](=O)[O-]

Procedure:
1-(3-Methylphenyl)tetrazole (11.3 g) was cautiously added at 0° to fuming nitric acid (100 cm3) with starting and the solution was then warmed on a steam bath for 5 minutes. The cooled solution was poured onto ice (200 g), and the solid material was filtered off, washed with water (100 cm3) and dried. Recrystallisation from ethyl acetate afforded 1-(3-methyl-4-nitrophenyl)tetrazole, m.p. 166°-168° (9.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Fc1ccc(I)cc1
Product: Fc1ccc(-n2ccc3ccc(Cl)cc32)cc1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-fluoro-4-iodobenzene: ESMS m/e: 245.9 (M+H)+.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:30]=[CH:29][C:13]([C:14]([C:16]2[C:17]([C:26](O)=[O:27])=[CH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:15])=[CH:12][CH:11]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[Cl:9][C:10]1[CH:30]=[CH:29][C:13]2[C:14](=[O:15])[C:16]3[C:17](=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:26](=[O:27])[C:12]=2[CH:11]=1
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccc(Cl)cc2C(=O)c2cc3ccccc3cc21
Temperature: 155 °C
Yield: 72.9 %

Procedure:
A 500 mL flask was successively loaded with trifluoromethanesulfonic acid (175 mL), 3-(4-chlorobenzoyl)-naphthalene-2-carboxylic acid (Formula XV, 25.5 g), and trifluoromethanesulfonic anhydride (21 mL). The mixture was heated at 155° C. for 10 hours. The violet-blue solution was gradually poured into a 2 L beaker containing 1 L of crushed ice. Additional ice was added as necessary to keep the solution cold. The brown-green mixture was poured onto a large 25-50 μm glass frit, and the isolated solid was washed with water (1 L), methanol (300 mL), and then air-dried overnight. The crude material was purified by high vacuum train sublimation (less than 10−3 Torr) at a source temperature of 165° C. to afford 17.5 g (73 percent yield) of bright yellow product. 1H NMR (400 MHz, d6-DMSO): δ 8.89 (‘s’, 6-H and 11-H), 8.36 (m, 4 lines, J=3.2 Hz, 7-H and 10-H), 8.30 (‘d’, J=8 Hz, 4-H), 8.22 (‘d’, 2 Hz, 1-H), 8.02 (‘dd’, J=2 Hz, 4 Hz), 7.82 (m, 4 lines, J=3.2 Hz, 8-H and 9-H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][O:21][CH3:22])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CCOC)CCNCC1
Reaction time: 2 h

Procedure:
4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8 g) was dissolved in methylene chloride (40 ml), trifluoroacetic acid (75.57 g, 50.72 ml) was added under an argon atmosphere at RT and the mixture was stirred for 2 hours until completion of the reaction. The reaction mixture was diluted with dichloromethane (500 ml), and then 3M NaOH (220.9 ml) was slowly added. The layers were separated, the organic layer washed with brine, dried over sodium sulphate and concentrated to give 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester a brown oil (3.76 g) which was essentially pure according to NMR and used in next reaction step without further purification. MS (ESI): 216.3 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:17]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 2-(methylamino)ethanol (2.14 mL, 26.6 mmol) in DCM (60 mL) was added triethylamine (4.1 mL, 29.3 mmol),N,N-dimethylpyridin-4-amine (1.63 g, 13.3 mmol) and tert-butylchlorodiphenylsilane (7.6 mL, 29.3 mmol). The reaction was stirred overnight at 40° C. After cooling to RT, the reaction was quenched with water (20 mL) and ether (100 mL). The organic phase was washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (4.4 g, 53%) as a colorless oil. NMR Spectrum (DMSOd6): 0.99 (s, 9H), 2.27 (s, 3H), 2.63 (t, 2H), 3.68 (t, 2H), 7.40-7.49 (m, 6H), 7.60-7.65 (m, 4H).
Reaction SMILES: CC(O)=O.[NH2:5][C@H:6]([CH3:9])[CH2:7][OH:8].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH3-]C#N.[Na+]>CO>[CH2:10]([NH:5][C@H:6]([CH3:9])[CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@@H](N)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Glacial HOAc (1.5 mL) was added dropwise at room temperature to a well stirred solution of (R)-(+)-2-amino-1-propanol (10.0 g, 133 mmol) and benzaldehyde (13.5 mL, 133 mmol) in CH3OH (260 mL). The reaction mixture was stirred at room temperature for 1.5 h followed by addition of NaCNBH3 (12.6 g, 200 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried over Na2SO4, filtered and concentrated to yield (R)-2-(benzylamino)propan-1-ol (19.8 g, 94%) as a colorless oil: MS consistent.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH:22]=O)=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([CH2:22][N:37]2[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]2)=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: OCCN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2cc(CN3CCN(CCO)CC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.5 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]phthalimide (45.0 mg, 0.111 mmol) was dissolved in acetonitrile (2 mL), and the solution was added with 1-(2-hydroxyethyl)piperazine (57 mg, 0.440 mmol), acetic acid (0.508 mL, 8.87 mmol) and sodium triacetoxyborohydride (118 mg, 0.557 mmol), followed by stirring at room temperature for 2.5 hours. The reaction mixture was added with water and sodium carbonate, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=4/1, 1/1) to obtain 3-amino-6-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl}phthalimide (22.2 mg, yield 38%).