Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[CH2:11]O)[CH3:2].O=S(Cl)[Cl:15]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:15][CH2:11][C:4]1[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:9][CH3:10]
Reactant: CCc1cccc(CC)c1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a mixture of (2,6-diethylphenyl)methanol (1.83 g, 11.1 mmol), toluene (20 mL) and DMF (6 drops) was added SOCl2 (2.1 g, 1.6 eq). The resulting solution was stirred at RT (1 h). After evaporating to dryness, the residue was taken up in heptane (−50 mL) and washed with water (−5 mL), dried (Na2SO4), filtered and evaporated to give 1.97 g (yield of 97%) of title product. 1H NMR (300 MHz, CDCl3) δ 1.28 (t, 6H), 2.79 (q, 2H), 4.70 (s, 2H), 7.09 (d, 2H), 7.20 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:46])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:36](=[O:45])[NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:27]2)=[CH:20][CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:46])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:36](=[O:45])[NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:27]2)=[CH:22][CH:23]=1
Reactant: CCN(CC)C1CCN(CC(C(=O)Nc2ccc(Cl)cc2)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C1CCN(CC(C(=O)Nc2ccc(Cl)cc2)c2ccc(/C=C/C(=O)Nc3ccccc3N)cc2)C1
Reaction time: 4 h

Procedure:
To a solution of (E)-[2-(3-{4-[1-(4-chloro-phenylcarbamoyl)-2-(3-diethylamino-pyrrolidin-1-yl)-ethyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (528 mg, 0.8 mmol) in CH2Cl2 (10 mL) was added CF3COOH (612 uL, 8 mmol). The mixture was stirred for about 4 h, and then NaHCO3 was added to the reaction system. After filtration of solids, the crude mixture was purified by preparative HPLC to obtain a light yellow solid. MS: calc'd 560 (MH+), exp 560 (MH+). 1H NMR (d4-MeOD, 400 MHz), 7.66 (d, 1H, J=15.6 Hz), 7.60-7.57 (m, 4H), 7.49 (d, 2H, J=8.0 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=7.6 Hz), 7.06 (t, 1H, J=7.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=15.6 Hz), 6.76 (t, 1H, J=7.6 Hz), 3.94 (m, 1H), 3.48-3.35 (m, 2H), 2.82-2.53 (broad m, 9H), 2.01-1.95 (m, 1H), 1.74-1.71 (m, 1H), 1.00 (q, 6H, J=7.0 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:2][C:3]2[N:4]=[N:5][C:6]3[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=3)[N:8]=2)[CH2:18][CH2:17]1
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2nnc3nc(N)nc(N)c3n2)CC1
Temperature: 80 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and N-methylpiperazine (2.00 mL) were heated to 80° C. in a sealed tube for 7 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 178 mg of yellow colored 3-(4-Methyl-piperazin-1-ylmethyl)-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].Cl[CH2:9][CH2:10][C:11]([N:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:19][CH:18]=1)[CH2:14][CH:15]=[CH2:16])=[O:12]>>[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10][C:11]([N:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:19][CH:18]=1)[CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:2][CH3:3]
Reactant: CCCNCCC
Reactant: C=CCN(C(=O)CCCl)c1ccc(-n2ccnc2)cc1
Product: C=CCN(C(=O)CCN(CCC)CCC)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 4, react dipropylamine with 3-chloro-N-[4-(1H-imidazol-yl)phenyl]-N-(2-propenyl)propanamide to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:33]([CH2:34][CH3:35])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37](=[O:39])[NH2:38].[ClH:40].CCOCC>ClCCl.CO.O1CCOCC1>[ClH:40].[NH2:1][C:2]1[N:33]([CH2:34][CH3:35])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])[N:9]=[CH:10][C:5]=2[C:4](=[O:36])[C:3]=1[C:37]([NH2:38])=[O:39]
Reactant: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3OC)nc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3ccc(C4CCNCC4)cc3OC)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.51 g (0.95 mmol) of the product prepared in step 4.4 is suspended in 10 mL of a dichloromethane/methanol mixture (v/v=8/2), and 3.55 mL (14.20 mmol) of a 4N solution of hydrogen chloride in dioxane are added. The mixture is stirred at room temperature overnight, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 0.48 g the expected product is obtained in the form of a beige-coloured solid, which is used as obtained in the following step. Yield (dihydrochloride)=99.1°A. m.p.=117°C. M+H+=408.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1>>[F:9][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Nc1cccnc1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Product: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cccnc1

Procedure:
Prepared according to Step D1 in General Procedure D using 1,3,5-trifluoro-2-nitrobenzene (5.28 mL, 45.2 mmol) and pyridin-3-amine (4.25 g, 45.2 mmol) to give N-(3,5-difluoro-2-nitrophenyl)pyridin-3-amine as a yellow solid. LC-MS (ESI) m/z 252.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH:13]([NH:15][CH3:16])[CH3:14])[N:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]2=[O:25].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:15]([CH:13]([C:10]2[N:9]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:8](=[O:25])[C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH3:14])[CH3:16])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CNC(C)c1nc2c(OC)cccc2c(=O)n1-c1ccc(OC)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3c(OC)cccc3c2=O)cc1

Procedure:
In a similar manner as described above in Paragraph A, 8-methoxy-3-(4-methoxyphenyl)-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[8-methoxy-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 536 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.O>Br>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Agent: Br
Solvent: O
Product: O=[N+]([O-])c1cc(O)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 79.5 %

Procedure:
10 g (44 mmol) of 4,5-dimethoxy-1,2-dinitrobenzene was suspended in 150 ml of 45% hydrobromic acid, and the suspension was refluxed at a boiling point for 6 hours. The reaction solution was allowed to cool to room temperature, and 500 ml of water was added thereto. The mixture was extracted three times with ethyl acetate. The organic layer was washed with a 10% sodium bicarbonate aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The crystal residue was washed with methylene chloride to obtain 7 g (yield: 79%) of 4,5-dihydroxy1,2-dinitrobenzene.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=1)=[O:7].[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]Br)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][N:2]([CH2:3][CH2:4][NH:5][C:6]([C:8]2[C:13]([NH2:14])=[N:12][C:11]([NH2:15])=[C:10]([Cl:16])[N:9]=2)=[O:7])[CH3:1])=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(CCCBr)cc1
Reactant: CNCCNC(=O)c1nc(Cl)c(N)nc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCCN(C)CCNC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid (2-methylamino-ethyl)-amide (Intermediate E) (0.97 g, 2.7 mmol) and [4-(3-Bromo-propyl)-phenoxy]-acetic acid methyl ester (Intermediate Q) (2.33 g, 8.12 mmol) in acetone (30 mL) is added sodium carbonate (0.86 g, 8.12 mmol), and the reaction is heated at reflux for 4 days. After this time, the reaction is allowed to cool to RT, filtered, and concentrated in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield {4-[3-({2-[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-methyl-amino)-propyl]-phenoxy}-acetic acid methyl ester. [M+H]+ 451.
Reaction SMILES: C1(C2N=C([C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:14])C=CC=2)C=CC=CC=1.[C:27]1([C:33]2[CH:37]=[C:36](C(O)=O)[NH:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([C:33]2[CH:37]=[C:36]([C:13]([C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:14])[NH:35][N:34]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cc(-c2ccccc2)n[nH]1
Reactant: COc1cc(C(=O)c2cccc(-c3ccccc3)n2)cc(OC)c1OC
Product: COc1cc(C(=O)c2cc(-c3ccccc3)n[nH]2)cc(OC)c1OC

Procedure:
(3-Phenyl-1H-pyrazol-5-yl)(3,4,5-trimethoxyphenyl)methanone (1k) was prepared using the same method as used of compound 1c from 3-phenyl-1H-pyrazole-5-carboxylic acid. 1H NMR (500 MHz, CDCl3 δ 10.97 (br, 1H), 7.77 (s, br, 2H), 7.48-7.38 (m, 5H), 7.14 (s, br, 1H), 3.96 (s, 3H), 3.94 (s, 6H); MS (ESI) m/z 361.1 (M+Na)+, 337.0 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([O:37]CC)=[O:36])=[CH:4]1)[CH3:2].[OH-].[K+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c(F)c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a suspension of ethyl 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (32 g, 59.8 mmol) in a mixture of Methanol (250 mL) and Water (125 mL) was added KOH (6.70 g, 120 mmol) portionwise. The resulting mixture was stirred at 90° C. for 3 h. LCMS indicated completion of the reaction. The mixture was cooled down to r.t. and concentrated. Water was then added, and the mixture was adjusted to pH ˜1 using 6 N aq. HCl. The precipitate was collected by filtration and dried to afford 1-ethyl-8-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (28 g, 55.2 mmol, 92% yield) as a yellow solid. LCMS (M+H)+: 508.2.
Reaction SMILES: C(OC([N:8]1[CH2:58][CH2:57][CH2:56][C@H:9]1[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:23][CH:22]=1)=[O:16])[CH3:14])=[O:11])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[ClH:53].[NH:8]1[CH2:58][CH2:57][CH2:56][C@H:9]1[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:25][CH:26]=1)=[O:16])[CH3:14])=[O:11]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 6 h

Procedure:
495 mg (0.588 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl 1-(tert-butoxycarbonyl)-L-prolyl-L-alaninate were dissolved in 3 ml dichloromethane, and 5.876 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 6 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 410 mg (90% of theory) of the target compound were obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2>>[N:23]1[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[C:16]2[C:20]([N:19]=[CH:18][NH:17]2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncnc2nc[nH]c12
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3nc[nH]c23)CC1
Yield: 92 %

Procedure:
Step 1: Example 136 was prepared by reacting BOC-piperazine with 6-chloropurine according to Example 1. Yield=92%, ES-MS: (M+H)+ 305.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[C:12]([C:20]#[N:21])=[CH:11]2)(=O)=O)C=CC=CC=1.[O:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[C:17]1[CH:18]=[C:13]2[C:12]([C:20]#[N:21])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#Cc1c[nH]c2ncc(-c3ccccc3Oc3ccccc3)cc12
Temperature: 105 °C
Yield: 40.3 %

Procedure:
A mixture of 8 (40.0 mg, 0.11 mmol), 2-phenoxyphenylboronic acid (35.5 mg, 0.166 mmol), PdCl2(PPh3)2 (7.8 mg, 0.011 mmol), LiCl (14.0 mg, 0.33 mmol), 1M Na2CO3 (276 μL, 0.28 mmol) in EtOH (0.66 mL) and toluene (0.66 mL) was heated at 105° C. for 0.5 h in a sealed reaction tube. Reaction mixture was separated between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (2×). The combined organic solutions were concentrated and purified by PTLC using ethyl acetate:hexane (1:1) as eluent to give 9 as a white solid (13.8 mg, 40%); 1H NMR (400 MHz, CDCl3) δ 12.80-12.60 (bs, NH), 8.69 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.87 (s, 1H), 7.53 (dd, J=7.6, 1.7 Hz, 1H), 7.40 (dt, J=7.5, 1.8 Hz, 1H), 7.29 (m, 3H), 7.06 (m, 2H), 6.94 (m, 2H); MS (CI) m/z 352.8 (MH+MeCN).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:25][CH:24]=1)=[O:22].[BH4-].[Na+].C(O)C>CN(C)C=O>[OH:22][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:27][CH:28]=1)[CH2:20][NH:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CCOC(=O)COc1ccc2c(c1)C[C@@H](N)CC2
Reactant: O=C(CBr)c1ccc(OC2CCCCO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)COc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OC3CCCCO3)cc1)CC2
Temperature: 0 °C
Yield: 82.8 %

Procedure:
Ethyl (S)-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl-oxy)acetate (1.14 g) was dissolved in N,N-dimethylformamide (15 ml), and 2-bromo-4'-((2RS)-2-tetrahydropyranyloxy)-acetophenone (600 mg) was added to the solution under ice-cooling with stirring, followed by reaction at room temperature for an hour. Sodium borohydride (380 mg) and ethanol (10 ml) were added to the reaction mixture under ice-cooling with stirring. After reaction for an hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The resulting residue was dissolved in tetrahydrofuran (20 ml), triethanolamine (2 ml) was added to the solution and the mixture was heated under reflux for 17 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate) gave ethyl 2-[(2S)-2-[[(2RS)-2-hydroxy-2-[4-((2RS)-2-tetrahydropyranyloxy)phenyl]ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetate (780 mg) as an oil.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)(O)[CH2:8][C:9]#[N:10])=[CH:3][CH:2]=1.CO>FC(F)(F)C(O)=O>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:2][CH:3]=2)=[CH:8][C:9]#[N:10])=[CH:17][CH:16]=1
Reactant: N#CCC(O)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#CC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Yield: 94.8 %

Procedure:
The crude carbinol 3,3-bis[(1,1-biphenyl)-4-yl]-3-hydroxypropanenitrile (13.5 g; 0.036 mol) was dissolved in trifluoroacetic acid (30 mL) and the solution was heated at 65° C. for 10 min. After the solvent was removed in vacuo, the residue was triturated with water and the resulting solids were dissolved in dichloromethane. The dried (MgSO4) solution was evaporated to provide 12.2 g of 3,3-bis[(1,1'-biphenyl)-4-yl]-2-propenenitrile as an oil that was contaminated with a small amount of starting ketone.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1>>[N+:28]([C:24]1[C:25]([NH2:27])=[N:26][C:21]([NH:19][CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:11])[CH2:17][CH2:16]2)=[CH:22][CH:23]=1)([O-:30])=[O:29]
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Nc1nc(NCC2CCN(S(=O)(=O)CCc3ccccc3)CC2)ccc1[N+](=O)[O-]

Procedure:
EXAMPLE 103 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 6-chloro-3-nitro-pyridin-2-ylamine: MS (m+1)=420.5.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH2:4][C@@H:3]([C:11]([O:13]CC)=[O:12])[N:2]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[C:20]1([CH2:19][O:18][C:16]([N:2]2[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH2:1]2)=[O:17])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CC2(CCOCC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethyl 2-(phenylmethyl) (3S)-8-oxa-2-azaspiro[4.5]decane-2,3-dicarboxylate (120) (300 mg, 0.86 mmol) in THF/water/methanol (3 mL/1.5 mL/1.5 mL) was added lithium hydroxide monohydrate (72 mg, 1.7 mmol) and the reaction stirred at room temperature for 30 min. The reaction was treated with 1N HCl (2 mL) and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the organic layer dried over MgSO4 and concentrated in vacuo to afford the title compound in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.54-12.93 (m, 1H) 7.21-7.47 (m, 5H) 4.90-5.20 (m, 2H) 4.11-4.41 (m, 1H) 3.44-3.70 (m, 5H) 3.24 (dd, J=15.0, 11.7 Hz, 1H) 2.32 (td, J=13.6, 8.5 Hz, 1H) 1.73 (ddd, J=16.8, 12.9, 7.2 Hz, 1H) 1.38-1.64 (m, 4H). LC-MS ESI (M−H)−=318.19.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=1.[CH2:17]([N:19](CC)CC)C.CN.C1COCC1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:13]([C:14]([NH:19][CH3:17])=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Oxalyl chloride (1.01 mL, 11.6 mmol) was added to a suspension of 4-chloronicotinic acid (prepared according to F. Guillier et al. J. Org. Chem. 1995, 60, 292) (1.5 g, 7.7 mmol) in CH2Cl2 (15 mL) containing 2 drops of DMF. The mixture was stirred at room temperature for 1 h then evaporated to dryness, suspended in CH2Cl2 (10 mL) and re-evaporated. The residue was re-suspended in CH2Cl2 (10 mL), cooled to 0° C. and treated with triethylamine (3.23 mL, 23.2 mmol) dropwise followed by a 2M solution of methylamine in THF (7.7 mL, 15.4 mmol) dropwise. The resulting orange mixture was stirred at 0° C. for 20 min before being concentrated in vacuo. The residue was treated with sat. NaHCO3 (aq) (30 mL), extracted with CH2Cl2 10×25 mL) and the combined organic layers were dried (MgSO4) and evaporated to give an orange oil which crystallised. The solid was triturated with ether (10 mL), stirred for 30 min, then filtered and washed with 1:1 ether/pentane (20 mL) to give the title amide (986 mg, 75%) as an off-white solid; δH (CDCl3, 400 MHz) 3.07 (3H, d), 6.20 (1H, br), 7.37 (1H, d), 8.53 (1H, d), 8.86 (1H, s).