Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CN(C)C=O.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH:25]=[CH:26][C:27]1[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[N:19]=[C:18]2Cl>O>[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH:25]=[CH:26][C:27]1[O:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)[N:19]=[C:18]2[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Nc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3cc(F)ccc3n2)o1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccccc3O)c3cc(F)ccc3n2)o1
Reaction time: 8 h
Yield: 95.6 %

Procedure:
An Erlenmeyer flask equipped with magnetic stirrer and oil bath for heating is charged with 5.0 g (0.046 mole) of o-aminophenol and 100 ml of dimethylformamide. The charge is stirred to dissolve o-aminophenol and 6.0 g (0.02 mole) of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) added. The reaction mixture is reacted at 80° to 90° C. for 2 hours to form an organic precipitate; 100 ml of water is added to the warm mixture which is then allowed to cool and placed overnight in a refrigerator to crystallize. The solids are collected, washed with methanol and dried to obtain 7.5 g of brown-tan solid. A solution of the product in 100 ml of dimethylformamide is treated with activated carbon and filtered. A first portion of 75 ml of methanol is added to the warm filtrate then an additional 25 ml portion. Cooling and scratching gives 5.5 g of orange crystals of the purified product.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCO>[ClH:1].[OH:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[CH:13]([C:12]([O:16][CH2:17][CH3:18])=[O:15])[NH:2][CH2:3][CH2:4]2
Reactant: NCCc1cccc(O)c1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2cc(O)ccc21
Yield: 90.1 %

Procedure:
A solution of 3-(2-aminoethyl)phenol hydrochloride (4.60 g, 26.49 mmol) and 47% ethyl glyoxylate/toluene solution (polymer form) (6.15 mL, 29.14 mmol) in a mixed solvent of toluene/EtOH (50 mL) was heated under reflux for 18 hr. The reaction mixture was concentrated under reduced pressure. The precipitate was collected by filtration, and washed with ethyl acetate/diethyl ether to give ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride (6.15 g, 23.86 mmol, 90%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7](Br)[C:5]=2[N:6]=1.[C:12]([Cu])#[N:13]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([C:12]#[N:13])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: N#C[Cu]
Reactant: Nc1nc2c(Br)cccc2s1
Solvent: CN(C)C=O
Product: N#Cc1cccc2sc(N)nc12

Procedure:
The title compound was prepared from 2-amino-4-bromo-1,3-benzothiazole by heating with CuCN (1.0 eq.) in DMF at 160° C. for 12 h.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].[CH:12]([Cl:15])(Cl)Cl>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:15][C:12]1[CH:2]=[N:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClC(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Clc1cnc2ccccc2c1

Procedure:
Indole (ex Aldrich) was reacted with chloroform and aqueous sodium hydroxide in the presence of triethylbenzyl ammonium chloride to give 3-chloroquinoline (cf. Sundo et al, Synthesis, 4, 249 (1976). The latter was converted to 2,3-dichloroquinoline, as for Example VII.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+].[Na+].[Cl-]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[O:27]=[S:24]1(=[O:28])[CH2:25][CH2:26][N:21]([C:2]2[N:7]=[C:6]3[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]3=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reactant: O=S1(=O)CCNCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(N3CCS(=O)(=O)CC3)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (420 mg, 1.19 mmol, Eq: 1.00) and thiomorpholine 1,1-dioxide (482 mg, 3.57 mmol) were combined with toluene (3 ml) to give a yellow solution. Bis(tri-tert-butylphosphine)palladium(0) (60.7 mg, 119 μmol) and sodium tert-butoxide (400 mg, 4.16 mmol, Eq: 3.5) were added. The reaction mixture was heated to 80° C. and stirred for 1 h. The reaction mixture was poured into 20 mL sat NaCl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 40% EtOAc in hexanes) to give 6-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (327 mg, 68%) as a yellow oil that solidified as off white solid upon standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:17])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:17][O:27]1)=[O:18])[CH3:2]
Reactant: C=C(CCCC1CCCCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCCCC2)CO1

Procedure:
2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1a) from 5.42 g of 5-cyclooctyl-2-methylenevaleric acid ethyl ester and 5.55 g of m-chloroperbenzoic acid in 50 ml of methylene chloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>O1CCCC1>[Si:9]([O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC#CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
60% Sodium hydride (1.39 g) was suspended in tetrahydrofuran (50 mL), and the suspension was cooled to 0° C., a solution of but-2-yne-1,4-diol (3.0 g) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-Butyldimethylsilyl chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0→80:20) to give the title compound (1.48 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)([CH3:15])[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)([CH3:15])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(C)(CCO)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 740 mg (1.84 mmol) of the compound from Example 104A in 20 ml of tetrahydrofuran was added dropwise to 5.5 ml (5.5 mmol) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 20 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 2 h and then water and dichloromethane were added, and the phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 437 mg (66% of theory) of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[CH:6][CH:5]=1.[CH3:30]I>CN(C)C=O.[Cl-].[NH4+]>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH3:29])([CH3:28])[CH2:26][O:27][CH3:30])=[CH:6][CH:5]=1
Reactant: CC(C)(CO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(C)(C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Sodium hydride (60% in oil, 10.2 mg, 0.255 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2-methylpropan-1-ol (90.3 mg, 0.213 mmol) in N,N-dimethylformamide (2.0 mL) at room temperature. After stirring 5 min, methyl iodide (45.1 mg, 0.320 mmol) was added to the mixture, and the mixture was stirred at room temperature for 50 min. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (71.5 mg, 0.163 mmol, 77%).
Reaction SMILES: CC([N:5]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([C@@H:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34](=[O:44])[C@@H:35]([NH:39][C:40]([O:42][CH3:43])=[O:41])[CH:36]([CH3:38])[CH3:37])[NH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])C(=O)[O-])(C)C.Cl>C(Cl)Cl>[NH2:5][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([C@@H:29]4[CH2:33][CH2:32][CH2:31][N:30]4[C:34]([C@@H:35]([NH:39][C:40](=[O:41])[O:42][CH3:43])[CH:36]([CH3:38])[CH3:37])=[O:44])[NH:27][CH:28]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CN(C(=O)[O-])C(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)c[nH]1)C(C)C

Procedure:
A solution of 1,1-dimethylethyl[2-(4′-{2-[(2S)-1-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-4-biphenylyl)-2-oxoethyl]carbamate (Intermediate 11) (3.8 g, 6.3 mmol) in DCM (40 mL) was treated with HCl (10 mL, 4M in dioxane) to give methyl {(1S)-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate (Intermediate 1) as light yellow solid (3.5 g, quant.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].CCN(CC)CC.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([O:29][CH3:30])=[CH:24][N:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.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.[Cu]I>[Cl:21][C:22]1[N:27]=[C:26]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:25]([O:29][CH3:30])=[CH:24][N:23]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1OC
Temperature: 120 °C

Procedure:
A solution of methyl 2-(2-ethynylphenyl)acetate (K1) (0.35 g, 2.0 mmol) in DMF (3 mL) and Et3N (0.70 mL, 5.0 mmol) was added to a mixture of 2,4-dichloro-5-methoxypyrimidine (0.30 g, 1.7 mmol), PdCl2(PPh3)2 (0.12 g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) and PPh3 (0.044 g, 0.17 mmol) in DMF (3 mL). The resulting mixture was heated under microwave irradiation at 120° C. for 15 minutes, then diluted with EtOAc and passed through a plug of Celite, washing with EtOAc (50 mL). The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-25% EtOAc in hexanes) to give the title compound A98 as a pale yellow solid (0.38 g, 72%); 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (dd, J=7.6, 1.0 Hz, 1H), 7.46-7.29 (m, 3H), 4.03 (s, 3H), 3.99 (s, 2H), 3.71 (s, 3H). LCMS-A: rt 5.92 min; m/z 317.1 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24](=[O:33])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(P(N(C)C)(N(C)C)=O)C.[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24](=[O:33])[CH:23]1[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(Cc2ccccc2)C(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a solution of 3.7 mL (26.6 mmol) of diisopropylethylamine in 55 mL of dry THF at −78° C. was added dropwise n-butyllithium (25 mmol, 10.0 mL of a 2.5 M solution in hexanes). The bath was replaced with an ice-water bath. After 20 min, the mixture was recooled to −78° C. and 3.10 g (11.86 mmol) of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate in a mixture of 20 mL of THF and 4.4 mL (24.4 mmol) of HMPA was added dropwise. After 2 h, 1.47 mL (12.4 mmol) of benzyl bromide was added dropwise, and the resultant mixture was allowed to warm slowly to ambient temperature overnight. The reaction was then quenched by the addition of 5 mL of saturated aqueous ammonium chloride solution. THF was removed in vacuo, and the residue was partitioned between ether and water. The organic phase was washed with 2 portions of brine and concentrated to give a red oil. Purification by Biotage chromatography (silica gel, 3% ethyl acetate/hexane) gave 1.96 g (47%) of the title compound as a light yellow mobile oil. LC-MS 352.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C>COCCOC>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=1
Reactant: CCN1CCCCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: COCCOC
Product: Clc1ccnc(N2CCCCC2)n1

Procedure:
A mixture of 2,4-dichloropyrimidine (1.0 g), 1-ethylpiperidine (1.099 mL) and 1,2-dimethoxyethane (10 mL) was refluxed for 6 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (553.1 mg).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C)=NC=1.[NH2:49][CH:50]([CH3:53])[CH2:51][OH:52]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:49][CH:50]([CH3:53])[CH2:51][OH:52])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: CC(N)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Agent: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Product: CC(CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 71 %

Procedure:
As described for example 220, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.31 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, using rac-2-amino-1-propanol instead of 3-amino-1-propanol, to the title compound (80 mg, 71%) which was obtained as a colourless gum. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].O1CCCCC1[O:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16]Cl>CS(C)=O.[Cl-].[Na+].O>[C:1]([CH2:16][CH2:15][CH2:14][C:13]#[C:12][CH2:11][OH:10])#[N:2]
Reactant: [C-]#N
Reactant: ClCCCC#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCC#CCO
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a stirred slurry of sodium cyanide (15 g, 306 mmol) in dimethyl sulphoxide (100 ml) preheated to 85° C., was added 1-tetrahydropyranyloxy-6-chloro-hex-2-yne (66.2 g, 306 mmol) at such a rate as to keep the temperature between 85° C. and 100° C. One hour after the addition was completed, the cooled mixture was slowly added to brine (600 ml) and extracted with ether (3×200 ml). The combined ether extracts were washed with further brine (200 ml) and dried over sodium sulphate. After removal of the solvent under reduced pressure, the reddish-brown oil was distilled and the fraction boiling between 140° and 160° C. (0.25 m.m.) collected and dissolved in methanol (200 ml). This solution was stirred overnight with 5 MH2SO4 (30 ml) and neutralised with solid potassium carbonate. The methanol was removed under reduced pressure and the residue partitioned between ether (200 ml) and brine (300 ml). The aqueous layer was extracted with further ether (2×300 ml). The combined organic extracts were washed with brine (2×100 ml) and dried over sodium sulphate. Removal of the solvent under reduced pressure, and distillation of the oil obtained gave 6-cyano-hex-2-yn-1-ol (22.0 g, 58%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6](=[S:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[NH:17][C:18]([NH:20][C:21]([O:23][CH3:24])=[O:22])=[S:19])=[O:4]>CO.O>[CH3:24][O:23][C:21]([NH:20][C:18](=[S:19])[NH:17][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[NH:7][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[S:25])[NH2:14])=[O:22]
Reactant: COC(=O)NC(=S)Nc1ccc([N+](=O)[O-])cc1NC(=S)NC(=O)OC
Solvent: O
Solvent: CO
Product: COC(=O)NC(=S)Nc1ccc(N)cc1NC(=S)NC(=O)OC
Temperature: 25 °C
Yield: 52.6 %

Procedure:
1,2-Bis-(3-methoxycarbonyl-2-thioureido)-4-nitrobenzene (9.7 g; 0.025 mole) and ferrous chloride tetrahydrate (1.13 g) were finely powdered together and suspended in a mixture of methanol (110 ml) and water (10 ml). The vigorously stirred suspension was then heated to reflux and reduced iron powder (6.53 g) was added in portions during five minutes. When the addition was complete, the reaction mixture was refluxed for a further forty five minutes and filtered. The dark brown filter cake was extracted with boiling methanol (2 × 120 ml), and the hot methanol solutions were combined with the hot aqueous methanol filtrate and evaporated to 200 ml. The solution was cooled to room temperature and the solid which separated was filtered off to give 3,4-bis-(3-methoxycarbonyl-2-thioureido)aniline (4.70 g), m.p. 186-187° C. (with decomposition), in the form of off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](Cl)=[O:52])[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([C:51](=[O:52])[NH:25][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH2:47][CH2:46]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A CH2Cl2 solution (111.0 mL) of C-(3-chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (1.9 g, 5.5 mmol) and PS-DIPEA (2.8 g, 11.1 mmol) in a round bottom flask under N2 atmosphere was charged with 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (1.4 g, 5.0 mmol) and stirred at rt for 1.5 h. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 10% CH3CN/CH2Cl2) to afford 4-{[(3-chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester as a pale yellow solid: MS (ES+): m/z 592/594 (100/50) [MH+]; HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[CH2:5]([N:4]([CH2:3][CH2:2][NH:1][C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCN(Cc1ccccc1)c1ccccn1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCN(Cc3ccccc3)c3ccccn3)[nH]c2=O)cn1

Procedure:
2-[N-(2-aminoethyl)-N-benzylamino]pyridine (0.95 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.91 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with ether and recrystallised from methanol to give 2-[2-(N-benzyl-N-pyrid-2-ylamino)ethylamino]-5-(6methylpyrid-3-ylmethyl) pyrimid-4-one, 1.02 g (68%) mp 178°-82° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13](O)=[O:14])[CH2:8][CH:7]=1.C(Cl)(=O)C([Cl:20])=O>>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([Cl:20])=[O:14])[CH2:8][CH:7]=1
Reactant: CC(C)=CCCC1=CCC(CC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)=CCCC1=CCC(CC(=O)Cl)CC1
Reaction time: 1 h

Procedure:
To a 100 mL flask containing a stirbar is added the acid 2B (R=4-Methyl-3-pentenyl) (10 g) and oxalyl chloride (8.3 mL). The reaction is stirred under a nitrogen atmosphere for one hour after gas evolution ceases. Residual oxalyl chloride is removed in vacuo.