Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:19])[CH2:14][CH2:13][N:12]1[C:29](OC(C)(C)C)=O)=O.C=O.C([BH3-])#N.[Na+].C1COCC1>C(O)(=O)C.O.CO>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[C@H:11]1[CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[O:19])[CH2:14][CH2:13][N:12]1[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1C(=O)Nc1ccccc1N
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CC[C@@H](NC(=O)Nc2ccc(C#N)cc2)C[C@@H]1c1nc2ccccc2[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
(2R,4R)-tert-butyl 2-((2-amino-phenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate (1600 mg, 3.34 mmol) was dissolved in acetic acid (10 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Trifluoroacetic acid (10 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and the resulting product was used in the next step without further purification. 37% formaldehyde solution (1.24 mL, 16.7 mmol) in water was added to a solution of the residue in methanol (20 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (10.5 mL, 10.5 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 18 hours and the solvent was evaporated under vacuum. Saturated sodium bicarbonate solution (50 mL), water (100 mL) and ethyl acetate (200 mL) were added and the mixture was stirred about 30 min. The organic layer was separated, dried over MgSO4, and concentrated. The resulting product was purified by Companion (ReadySep 40 g, silica gel packed) using CH3OH/CH2Cl2 from 1-5% as eluent to provide the title compound as an off-white solid 915 mg (73%). LC-MS: 375.3, 373.3 (t=1.5 min). 1H NMR (acetone-D6): δ 1.81 (m, 2H), 1.9-2.05 (m, 2H), 2.10 (m, 1H), 2.17 (s, 3H), 2.52 (m, 1H), 2.94 (m, 1H), 3.86 (m, 1H), 4.2 (m, 1H), 6.4 (d, 1H), 7.16 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.62 (m, 2H), 8.46 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35](O)=[O:36])[C:25]1=[O:26].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:24]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]([C:35]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:36])[C:25]1=[O:26]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)c1cc2ccccc2oc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1cc2ccccc2oc1=O
Yield: 72.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), coumarin-3-carboxylic acid (2.3 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (2.8 g, 71%) as crystals.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=2[CH:13]=1)=[O:11].C(N(CC)CC)C.O>O1CCCC1>[C:1]([N:18]1[CH2:17][CH2:16][C:15]2[CH:21]=[CH:22][C:12]([C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][Cl:5])=[CH:13][C:14]=2[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(CCCCCl)c1ccc2c(c1)CCNCC2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(C(=O)CCCCCl)cc2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetyl chloride (679 μl) was added to a solution of 5-chloro-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (2.2 g) obtained in Reference Example 121 and triethylamine (1.67 ml) in tetrahydrofuran (30 ml). After stirring at room temperature for 60 minutes, water (50 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give an oil (2.54 g).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][C:41]#[CH:42]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:39][CH2:40][C:41]#[CH:42])=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: C#CCN
Product: C#CCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.9 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 568 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][NH:13]1>C(O)C>[OH:10][CH2:11][C@@H:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][N:13]1[C:2](=[S:3])[NH:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C=Nc1cccnc1
Reactant: OC[C@@H]1Cc2ccccc2CN1
Solvent: CCO
Product: OC[C@@H]1Cc2ccccc2CN1C(=S)Nc1cccnc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
3-Isothiocyanatopyridine (6.8 g.) is added to a solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (8.15 g.) in ethanol (150 cc.). After 3 hours at a temperature of about 20° C., the solution is cooled to 0° C. The white crystals which have appeared are filtered off and are then recrystallised from propanol (200 cc.). After filtration, the crystals are washed with propanol (2 × 10 cc.) and then dried at 60° C. under reduced pressure (1 mm. Hg). (S)-3-Hydroxymethyl-N-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (12.1 g.) melting at 192° C is thus obtained.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[N:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[OH:13][C:3]1([C:1]#[C:2][C:22]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:30])[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (592 mg, 3.25 mmol) in tetrahydrofuran (6 mL), 2.63 M n-butyllithium (solution in n-hexane, 2.6 mL, 6.82 mmol) was added dropwise at −78° C. for 5 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. Thereafter, a solution of N-methoxy-N-methyl-6-methyl-nicotinamide (614.5 mg, 3.41 mmol) in tetrahydrofuran (5 ml) was added dropwise at −78° C. for 20 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (626.3 mg, 2.08 mmol, 65%) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[OH:14][CH2:15][C:16](O)=O>>[CH3:1][N:2]1[C:3]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[N:6]3)[N:13]=[C:16]1[CH2:15][OH:14]
Reactant: CNc1ccc2nccnc2c1N
Reactant: O=C(O)CO
Product: Cn1c(CO)nc2c3nccnc3ccc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of N6-methylquinoxaline-5,6-diamine (1.14 g, 6.4 mmol) and 2-hydroxyacetic acid (486 mg, 6.4 mmol) was stirred at 110° C. for 2 h. Then the mixture was purified by silica gel column chromatography (eluting with DCM/MeOH v/v 30:1) to give (3-methyl-3H-imidazo[4,5-f]quinoxalin-2-yl)methanol as a yellow solid (880 mg, yield 39%). ESI MS: m/z 215.1 [M+H]+.
Reaction SMILES: C(OC([N:7]1[CH:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9][C@H:8]1[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=O)C=C.O.CCCC[SnH](CCCC)CCCC>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>[Si:19]([O:18][CH2:17][C@@H:8]1[CH2:9][C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:11][NH:7]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: C=CCOC(=O)N1C=C(CC(=O)OC)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Product: COC(=O)CC1=CN[C@H](CO[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A catalytic amount of PdCl2(PPh3)2 (84 mg, 0.12 mmol) was added to a stirred solution of the allyl carbamate 17 (1.10 g, 2.98 mmol) and H2O (0.32 mL, 17.8 mmol) in CH2C2 (36 ml). After 5 minutes stirring at room temperature, Bu3SnH (0.89 mL, 0.96 g, 3.30 mmol) was added rapidly in one portion. A slightly exothermic reaction with vigorous gas evolution immediately ensued. The mixture was stirred for 16 hours at room temperature under nitrogen at which time TLC (50% EtOAc/Petroleum Ether) revealed the formation of amine along with the complete consumption of starting material. After diluting with CH2Cl2 (30 mL), the organic solution was dried (MgSO4), filtered and evaporated in vacuo to give an orange oil which was purified by flash chromatography (50% EtOAc/Petroleum Ether) to afford the enamine 18 as a slightly orange oil (0.57 g, 67%): 1H NMR (270 MHz, CDCl3) δ 7.53 and 7.48 (br s×2, 1H, NCH═CCH2CO2CH3), 4.35-4.13 (m, 1H, NCHCH2OTBDMS), 3.82-3.17 (m, 7H, NCH═CCH2CO2CH3, NCHCH2OTBDMS and CO2CH3), 2.64-2.04 (m, 2H, NCH═CCH2CO2CH3CH2), 0.90-0.88 (m, 9H, SiC(CH3)3), 0.09-0.00 (m, 6H, Si(CH3)2); MS (EI), m/z (relative intensity) 285, (M+., 1), 270 (M-CH3, 7), 254 (6), 242 (4), 230 (6), 228 (M-tBu, 100), 212 (4), 196 (3), 168 (13), 115 (3), 89 (10), 80 (4), 73 (13); MS (CI), m/z (relative intensity) 342 (M+.+57, 7), 302 (M+.+17, 7), 286 (M+.+1, 100), 228 (M-tBu, 100).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:14](=[O:39])[NH:15][CH:16]([C:32](=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH:16]([NH:15][C:14](=[O:39])[CH:9]([NH:7][CH3:6])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:32](=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:19][CH:20]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.25 h

Procedure:
[S-(R*,R*)]-{1-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester (4.0 g, 7.24 mmol) was dissolved in CH2Cl2 (24 mL) and treated with trifluoroacetic acid (16 mL). The reaction was stirred for 15 minutes, then concentrated, diluted with EtOAc (300 mL), washed with bicarbonate solution (3×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 8% MeOH/CH2Cl2 to give 2.8 g (85%) of [S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[O:14]1[CH2:18][C:17](=O)[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]1=2.Cl>O1CCCC1>[C:12]([CH2:11][C:17]1[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH:18]=1)#[N:13]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1COc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1coc2ccccc12
Temperature: 70 °C
Yield: 8.7 %

Procedure:
To a suspension of 27 gms (1.12 mole) of oil free sodium hydride in 400 ml of tetrahydrofuran (THF) was added dropwise a solution of 199.2 gms (1.12 mole) of diethylcyanomethylphosphonate in 400 mL of THF. After the H2 evolution had ceased, a solution of 150.1 g (1.12 mole) of 3-(2H)-benzo[b]-furanone in 1 L of THF was added. The solution was heated at 70° C. for 1.5 hours, cooled, and poured into 500 mL of 5% HCl, and washed with ether. The ether phase was washed with brine, dried (MgSO4), filtered and concentrated to give 15.4 g of a dark oil. The product was distilled at 110°-120° C./0.7 Torr Hg to give 116 g (66% yield) of a yellow oil which crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:23]C)=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1.[Br:25]Br>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[C:14]([Br:25])[CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: BrBr
Reactant: COc1cc2c(cc1Cl)CCN(C)CC2c1cccc2c1OCC2
Solvent: CC(=O)O
Product: CN1CCc2cc(Cl)c(O)cc2C(c2cc(Br)cc3c2OCC3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(+) 8-Chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.0 g, 2.9 mmol) was dissolved in acetic acid (10 ml). To the stirred solution was added bromine (0.20 ml, 4.0 mmol) in acetic acid (5 ml) over a period of 2 h. The mixture was stirred overnight at room temperature. A precipitate was formed. The white solid was filtered and washed with diethylether.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.S(=O)(=O)(O)O.[NH4+].[N:21]#[C:22][S-:23].Cl>[Fe].O>[NH2:21][C:22]1[S:23][C:2]2[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N:12]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1[N+](=O)[O-]
Reactant: N#C[S-]
Agent: [Fe]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nc2cc(S(=O)(=O)O)ccc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
218 g 2-amino-nitrobenzene-5-sulfonic acid were added to 1100 ml of a 1.0 Molar Sulphuric acid at 5° C. and diazotated. The resulting suspension was slowly added to a solution of 180 ml water, 152 g NH4SCN and 5 g Cu(SCN)2 at 0 to 5° C. and stirred for additional 3 hours at room temperature. The reaction mixture was poured into a hot (90 to 95° C.) suspension of 1000 ml water, 500 g iron powder and 17 g of a 37% hydrochloric acid and the resulting suspension was stirred till the reduction was completed. The mixtures was brought to a pH of more than 9 and the iron slurry was filtered off. The product was precipitated by lowering the pH, filtered off, washed and dryed. This yields 200 g product (2-Amino-benzthiazole-5-sulfonic acid) as an press cake.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:22]([F:25])([F:24])[F:23])=[C:5]([C:20]#[N:21])[C@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:7]=1[C:8]#[N:9].[OH-].[K+:27]>C1COCC1>[C:8]([C:7]1[C@@H:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[CH3:19])[C:5]([C:20]#[N:21])=[C:4]([C:22]([F:23])([F:25])[F:24])[N-:3][C:2]=1[CH3:1])#[N:9].[K+:27]
Reactant: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)[N-]1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 39 mg (0.11 mmol) (4R)-2-methyl-4-(3-methyl-1H-indazol-5-yl)-6-(trifluoromethyl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 5) in THF (2 ml) under argon atmosphere was added 126 μl (0.12 mmol) 1 N aqueous potassium hydroxide solution, and the mixture was stirred under a weak argon stream for 5 days at room temperature. The resulting precipitate was dried in vacuo to yield 44 mg (100% of th.) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[CH3:19][NH:20][CH2:21][CH3:22]>CO>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([CH2:21][CH3:22])[CH3:19])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: CCNC
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CCC2
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1CCCC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2,4-dichloro-8-phenyl-5,6,7,8-tetrahydroquinazoline (53.9 mg, 0.193 mmol) in methanol (1 mL) was added N-methylethanamine (0.033 mL, 0.386 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-chloro-N-ethyl-N-methyl-8-phenyl-5,6,7,8-tetrahydroquinazolin-4-amine (42.9 mg, 0.141 mmol, 72.9% yield) as colorless oil. LC-MS (M+H)+=302.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.25 (2H, t, J=7.5 Hz), 7.13-7.20 (1H, m), 7.01 (2H, d, J=7.3 Hz), 4.06-4.14 (1H, m), 3.42-3.53 (2H, m), 3.05 (3H, s), 2.56-2.74 (2H, m), 2.17-2.27 (1H, m), 1.76-1.89 (2H, m), 1.52-1.64 (1H, m), 1.24 (3H, t, J=7.2 Hz).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH2:9][C@@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](COCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd—C (wet, 3.6 g), and the resulting mixture was stirred at rt under a H2 balloon overnight. After filtration, the solvent was removed under vacuum, and the residue was purified by flash column chromatography to give (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.84 g, 99%) as a clear oil. 1H NMR (400 MHz, CDCl3): 3.88 (d, 2H), 3.82 (br, 1H), 3.64 (d, 1H), 3.56 (m, 3H), 2.94 (m, 1H), 2.76 (m, 1H), 1.90 (br, 1H), 1.44 (s, 9H); MS m/z 218 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1[C:39]2[C:34](=[CH:35][C:36]([C:40]3C=CC=CC=3)=[CH:37][CH:38]=2)N=C(N2C=C(C(O)=O)C=N2)N1.CC1C=CC=CC=1B(O)O>>[O:27]=[C:19]1[C:18]2[C:13](=[CH:14][C:15]([C:35]3[CH:34]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:40])=[CH:16][CH:17]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20]1
Reactant: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Agent: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc2c(=O)[nH]c(-n3cc(C(=O)O)cn3)nc2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 2-methylphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O3, 346.1; m/z found, 347.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.82 (br s, 1H), 8.92 (s, 1H), 8.10 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.47 (s, 1H), 7.36-7.27 (m, 5H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10](Br)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 31.2 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid tert-butyl ester (Intermediate 50, 0.195 g, 0.53 mmol), triethyl amine (2 mL), copper(I)iodide (0.040 g, 0.2 mmol), trimethylsilyl acetylene (0.3 mL, 2.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.13 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.064 g, 32%) was obtained as a brown oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]([O:12]C)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([C:4]2[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ncccc1C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncccc1C1CC1

Procedure:
To a solution of methyl 3-cyclopropylpyridine-2-carboxylate (80 mg, 0.45 mmol) in THF (2 ml) and water (2 ml) was added lithium hydroxide (55 mg, 1.36 mmol) and the reaction mixture was refluxed for 2 hours. The reaction was then acidified to pH 2 using 1M HCl (aq) and extracted with DCM (3×50 ml). The combined organics were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-])=O.[H][H]>C(O)C.[Pd]>[NH:1]1[C:4]2=[CH:5][N:6]=[CH:7][CH:8]=[C:9]2[CH:10]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ccncc2[nH]1
Yield: 83.5 %

Procedure:
1.8 g of 10% palladium-on-charcoal are charged into an autoclave, the atmosphere of which is then made inert with a stream of argon. A solution of 6 g of ethyl 3-(3-nitro-4-pyridyl)-2-oxopropionate in 72 mL of absolute ethanol is added. The reaction medium is then stirred for 3 hours at 20° C. under a pressure of 2 bar of hydrogen. The mixture is then filtered through Celite®. The filtrate is concentrated under reduced pressure and oven-dried at 40° C. to give 4 g of ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate, the characteristics of which are as follows: