Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([OH:21])=O)=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19]([Cl:30])=[O:21])=[CH:4][CH:3]=1
Reactant: CSc1ncc2cc(C(=O)O)n(-c3ccc(F)cc3)c2n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, 24, (4.7 g, 15.5 mmol) in dichloromethane (100 mL) is added DMF (0.5 mL) followed by dropwise addition of oxalyl chloride (2.7 mL, 31.1 mmol). The mixture is allowed to slowly warm to room temperature over a period of 3 hours. The reaction mixture is concentrated in vacuo and can be dried azeotropically with toluene to afford 4.7 g of the desired product, which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 9.38 (s, 1H), 8.04 (s, 1H), 7.40-7.20 (m, 4H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 322.0 (100, M++H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:7]([F:17])=[CH:6][C:5]=2Br.[OH-].[Na+].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:7]([F:17])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(N3CCOCC3)c(F)cc(Br)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Yield: 65.7 %

Procedure:
To a solution of 24 g of 2-methyl-4-morpholino-5-fluoro-7-bromoindole in 200 ml of ethanol was added 1 of palladium-carbon and then 15 ml of a 20% aqueous sodium hydroxide solution. This mixture was subjected to catalytic reduction at room temperature and at atmospheric pressure. The reaction was stopped when a theoretical amount (about 1.7 l) of hydrogen was absorbed, and the catalyst was removed by filtration followed by concentration. The residue was purified through silica gel column chromatography (Wako gel C-200; eluent: chloroform: n-hexane=5:1) to give 11.8 g of 2-methyl-4-morpholino-5-fluoroindole.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[NH:15]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:16]([C:18](O)=[O:19])[CH3:17]>C1COCC1>[NH:15]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:16]([C:18]([NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:19])[CH3:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Phenylalanine methyl ester hydrochloride (0.5 g, 2.3 mmol) was suspended in 10 mL of dry THF. Et3 n (0.35 mL, 2.5 mol) was added, after which both CBZ-Ala (10, 0.52 g, 100 mol %) and 1 (0.65 g, 104 mol %) were also added. The reaction mixture was stirred for 24 h at room temperature. Following the general procedure gave 21, 0.74 g, 84%, as a crystalline solid. An identical reaction using DMF as the solvent produced 21 in 93% yield: mp 97°-98° C.; [α]25D -8.3° (c 0.3, EtOH); 1H NMR δ 7.42-7.15 (m, 10H), 6.40 (d, 1H, J=4), 5.24-5.21 (m, 1H), 5.10 (s, 2H), 4.88-4.84 (m, 1H), 4.24-4.21 (m, 1H), 3.78 (s, 3H), 3.16-3.13 (m, 2H), 1.38 (d, 3H, J=7). Anal. Calcd for C21H24N3O5 : C, 65.5; H, 6.3,; N, 7.3. Found: C, 65.5; H, 6.3; N, 7.3. Compound 21 was also synthesized from the reaction of 11 and isourea 2 (R=M1) in DMF (82% yield) and was identical to material formed above.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:11])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 4-chlorobenzyl alcohol (14.26 g, 100 mmol) in CH2Cl2 (40 mL) at ambient temperature was added added dropwise a solution of PBr3 in CH2Cl2 (1.0M, 32 mL, 32 mmol). The reaction mixture was stirred for 72 hours at ambient temperature and then was poured slowly onto ice. The layers were separated and the organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-chlorobenzyl bromide (19.76 g) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1>[OH:24][C@@H:13]1[CH:14]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:15][C@@:16]2([CH3:17])[C:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH3:2])=[CH:12]1
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=C[C@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@H](O)C(N5CCOCC5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
21-Bromo-3α-hydroxypregn-4-ene-11,20-dione (150 mg.) in tetrahydrofuran (5 ml.) was treated with morpholine (0.1 ml.) and the stirred mixture was refluxed under nitrogen for 2 hours, during which time a white precipitate formed. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with more methylene chloride and the combined organic extracts were washed with water, dried over sodium sulphate and evaporated to a foam (152 mg.) which was purified by preparative T.L.C. in acetone/petrol 1/1, the main band Rf 0.3-0.45 being separated to give title compound (99 mg.) as a white foam, [α]D + 174° (c 0.12)
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][C:11]=1[O:24][CH:25]([CH3:27])[CH3:26])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOC(C)=O.CCO>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[O:24][CH:25]([CH3:27])[CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Oc1cc(O)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 10% palladium on carbon (0.543 g, 0.510 mmol) in a solution of 4-(benzyloxy)-2-isopropoxyphenyl benzoate (3.70 g, 10.21 mmol) in EtOAc (25 mL) and EtOH (5 mL) was shaken in a Parr shaker under H2 (45 psi) at 25° C. for 3 days. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 25% EtOAc in hexanes over 4536 mL) to afford 4-hydroxy-2-isopropoxyphenyl benzoate. Rf=0.28 (20% EtOAc in hexanes). LCMS calc.=295.10; found=295.07 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 8.22 (d, j=7.8 Hz, 2 H); 7.64 (t, J=7.4 Hz, 1 H); 7.51 (t, J=7.7 Hz, 2 H); 6.94 (d,J=8.6 Hz, 1 H); 6.49 (d, J=2.7 Hz, 1 H); 6.35 (dd, J=8.6, 2.7 Hz, 1 H); 4.39 (p, J=6.1 Hz, 1 H); 1.22 (d, J=6.1 Hz, 6 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si:21]([CH2:24][Mg]Cl)([CH3:23])[CH3:22].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(O)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=1[O:17][CH3:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C[Si](C)(C)C)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of (2-methoxy-5-nitro-phenyl)-carbamic acid tert-butyl ester (1.80 g, 6.71 mmol) in THF (50 mL) was added ((trimethylsilyl)methyl)magnesium chloride (2.47 g, 16.8 mmol) at −70° C. under nitrogen gas. The solution was then stirred at −70° C. for one hour. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.05 g, 13.4 mmol) in THF (30 mL) was added, the reaction was warmed to 0° C. The reaction was allowed to stir at 0° C. for another hour. The reaction mixture is poured into an aqueous solution of acetic acid (50 mL, 5%). The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave brown oil. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (2-methoxy-5-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.50 g, 63%) as a light oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH2:20][CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12]2)[CH:5]=1.[OH-].[Li+]>>[O:15]1[C:14]2([CH2:19][CH2:20][N:11]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[CH3:10])[C:3]([OH:21])=[O:2])[CH2:12][CH2:13]2)[O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(C)c(N2CCC3(CC2)OCCO3)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(C(=O)O)cc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid methyl ester (100 mg, 0.343 mmol] in 3 ml of mixed solvent [1:0.3:0.5 THF/water/methanol] was treated with lithium hydroxide (12.25 mg, 0.514 mmol]. The reaction mixture was stirred at room temperature for 6 hours, concentrated and acidified [pH=4] with 2M HCl. The precipitate obtained was filtered, washed with water and dried under vacuum. The crude material was washed with ether, air dried overnight to give desired product. i.e., 3-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-4-methyl-benzoic acid [12] as yellow colored solid. On the basis of mass recovery (93.2 mg) the yield was assumed to be quantitative.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH:15]=[O:16]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C=O)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.1 %

Procedure:
4.18 g of manganese dioxide were added to a solution of 0.87 g of 1,4-dimethoxy-2-naphthylmethanol (prepared as described in Preparation 20) in 10 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 6.5 hours. At the end of this time, the reaction mixture was filtered to remove inorganic materials, and the filtrate was dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting crystalline residue was washed with hexane and air-dried, to give 0.57 g of the title compound as pale yellow needles, melting at 120°-123° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]1([N:21]([CH3:28])[S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:29]([C:37]1[CH:38]=[CH:39][C:40]([N+:45]([O-:47])=[O:46])=[C:41]([CH:44]=1)[CH:42]=O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCCl>[CH:15]1([N:21]([CH3:28])[S:22]([CH2:25][CH2:26][NH:27][CH2:42][C:41]2[CH:44]=[C:37]([C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:38]=[CH:39][C:40]=2[N+:45]([O-:47])=[O:46])(=[O:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CN(C1CCCCC1)S(=O)(=O)CCN
Reactant: O=Cc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH(OAc)3 (0.014 mol) was added to a mixture of 2-amino-ethanesulfonic acid cyclohexyl-methyl-amide (0.0091 mol) and 5-benzoyl-2-nitro-benzaldehyde (0.0091 mol) in DCE (150 mL). The reaction mixture was then stirred overnight at room temperature and then washed with saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](C)(C)(C)[CH3:34].[OH-].[NH4+]>CN(C=O)C.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>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:34])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2(CC1CS(=O)(=O)c1ccc(Br)cc1)OCCO2)OCc1ccccc1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CC2CC3(CCC2NC(=O)OCc2ccccc2)OCCO3)cc1
Temperature: 75 °C

Procedure:
[7-(4-Bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester from example (3e) (1.0 g), was dissolved in DMF (10 ml) prior to the addition of PdCl2(PPh3)2 (54 mg) and Sn(Me)4 (0.32 ml), and a few crystals of 2,6-tert-butyl-4-methylphenol. The resulting solution was heated in an oil bath at 75° C. for 32 h. After cooling to rt, 10% ammonium hydroxide(aq) was added. The reaction was extracted with EtOAc twice. The combined organic layer was washed with brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (7R, 8S)-([7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (668 mg). MS found: (M+H)+=460.3.
Reaction SMILES: [OH:1][CH:2]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:1][CH:2]([CH2:12][NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH2:3][NH:4][C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To a solution of di-tert-butyl (2-hydroxy-1,3-propanediyl)biscarbamate (200 g) in methylene chloride (1.2 L) was added triethylamine (384 ml) under cooling on an ice-water bath and then a solution of methanesulfonyl chloride (64 ml) in methylene chloride (300 ml) was dropwise added at a temperature below 15° C. The mixture was stirred at the same temperature for 1.5 hours and quenched with saturated aqueous sodium hydrogencarbonate solution (200 ml). The organic layer was made acidic (pH=3) with diluted hydrochloric acid, and washed with saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with ethyl acetate (100 ml)—hexane (500 ml) to give 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (202 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([OH:33])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33][CH3:34])[CH:30]=[CH:29]3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@H]3C=C[C@@H](O)C3)c3ccccc3n2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO[C@@H]1C=C[C@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Yield: 91 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline [cf. Example 35(3)] (6.31 g) and methyl iodide (4.00 g) in dimethylformamide (52 ml) is added 60% sodium hydride (in oil) (678 mg) with stirring under ice-cooling, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=500:1, v/v) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,4S)-(4-methoxycyclopent-2-en-1-yl)oxy]quinazoline (5.92 g) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:34])[C:32]#[CH:33]>C(NCC)C.C(Cl)Cl.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:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:33]=[C:32]([CH2:31][OH:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CO)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a solution of N-(4-chlorobenzyl) -4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.15 g), PdCl2(PPh3)2 (0.0098 g) and CuI (0.0027 g) in diethylamine (5.2 mL) and CH2Cl2 (5 mL) is added propargyl alcohol (0.016 mL). The reaction is stirred at room temperature overnight, then concentrated. The crude residue is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are dried over Na2SO4 and condensed. The crude product is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 2.5% MeOH/ICH2Cl2) Product containing fractions are combined and concentrated. The resulting solid is triturated with CH2Cl2/hexanes, filtered and dried to yield 0.029 g (23%) of N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, m.p. 210-212° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([OH:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[K+].[Br:21]Br>C(O)(=O)C>[Br:21][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]=1[OH:15]
Reactant: BrBr
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])cc(Br)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
1.74 kg (8.2 mol) of ethyl 5-nitrosalicylate and 700 g of potassium acetate were dissolved in 5000 ml of acetic acid. 1.312 kg of bromine was dropwise added to the obtained solution at room temperature in one hour. Thereafter, the resulting mixture was further stirred for one hour and then concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate. The obtained solution was washed with water, dehydrated and concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 2.38 kg of the title compound as a colorless crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]([C:9](=[O:14])[C@@H:10]([O:12][CH3:13])[CH3:11])[N:7]=[C:6]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:5]1.[N:29]#[C:30]Br.C(N(CC)CC)C>ClCCl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:6]1[S:5][C:4]([CH2:3][CH2:2][NH:1][C:30]#[N:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]([C:9](=[O:14])[C@@H:10]([O:12][CH3:13])[CH3:11])[N:7]=1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCN)c1ccccc1
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCNC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-1-(2-(2-aminoethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (34.5 mg, 0.0721 mmol) and cyanogen bromide (9.9 mg, 0.0938 mmol) in dichloromethane (1 mL) was slowly added triethylamine (25.5 mg, 0.252 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to provide the crude product that was used without further purification.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH3:24]>>[NH2:24][N:11]1[C:12](=[O:13])[C:6]2[C:7](=[N:8][CH:3]=[N:4][CH:5]=2)[N:9]=[C:10]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: N
Product: CCCOc1ccccc1-c1nc2ncncc2c(=O)n1N
Reaction time: 8 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.55 g) was heated in ethanolic ammonia (50 ml) in a pressure vessel for 8 hours at 90° C. and then for 8 hours at 145° C. After cooling a grey solid (0.64 g) was collected and was recrystallised from ethanol (with charcoal) to yield a crude product (0.47 g) which was recrystallised from ethanol to yield the title compound, 0.29 g, m.p. 261°-262° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=O)=[CH:18][C:17]=3[CH:28]=2)=[CH:9][CH:8]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([NH:22][C:16]4[CH:17]=[CH:28][C:13]([CH2:36][N:34]([CH3:33])[CH:35]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:14][CH:15]=4)=[O:27])=[CH:18][C:17]=3[CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (10 ml) was dissolved 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine 4-carboxylic acid (0.18 g). To the solution was added, under ice-cooling, thionyl chloride (0.09 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (20 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.12 g) and triethylamine (0.33 ml) in THF (10 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 1) (0.23 g) as colorless crystals.