Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[N:2].[NH2:8][OH:9]>CCO>[OH:9][NH:8][C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)=[NH:2]
Reactant: NO
Reactant: N#Cc1ccco1
Solvent: CCO
Product: N=C(NO)c1ccco1
Temperature: 80 °C

Procedure:
2-Cyanofuran (150 mg, 1.61 mmol) was dissolved in EtOH (1.61 mL) and treated dropwise with aq. hydroxylamine (50% w/w, 296 μL, 4.83 mmol) at room temperature. The mixture was warmed at 80° C. for 1.5 h. Upon completion, the solvent was removed to afford a colorless oil that was used without purification (203 mg, quant.): 1H NMR (CDCl3, 500 MHz) δ 9.34 (br s, 1H), 7.42 (d, 1H, J=1.1 Hz), 6.79 (d, 1H, J=3.3 Hz), 6.42 (dd, 1H, J=1.8, 3.4 Hz), 5.09 (br s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34](O)=[O:35])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.[NH2:37][C@@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]1>>[C:47]([O:46][C:45](=[O:51])[NH:44][C@H:41]1[CH2:40][CH2:39][C@@H:38]([NH:37][C:34]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:7]4[CH:8]=[C:9]([C:12]([F:13])([F:15])[F:14])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:17]=3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:23]=2[CH3:33])=[O:35])[CH2:43][CH2:42]1)([CH3:50])([CH3:48])[CH3:49]
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c8) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:20]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:20])=[CH:9][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN(CCOc1ccc(O)cc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCN(CCOc1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 3 (78 mg, 0.3 mmol), K2CO3 (95 mg, 0.69 mmol), in acetone (50 mL), 1 mL (16 mmol) of MeI was added. The reaction mixture was heated to reflux for 48 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 50 mL water. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/CH2Cl2 (2/1) to provide compound 24 (49 mg, 0.18 mmol, 60% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.23 (m, 2H), 6.83 (m, 4H), 6.73 (d, J=8.4 Hz, 2H), 6.68 (t, J=7 Hz, 1H), 4.07 (t, J=6.4 Hz, 2H), 3.77 (s, 3H), 3.70 (t, J=6.4 Hz, 2H), 3.47 (q, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 153.93, 152.91, 147.62, 129.38, 115.95, 115.40, 114.67, 111.80, 66.01, 55.74, 49.76, 45.59, 12.30; HRMS (ESI, positive) m/z calcd. For C17H22NO2 [M+H]+: 272.1645, found: 272.1646.
Reaction SMILES: C([N-][CH:5]([CH3:7])[CH3:6])(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]([O:25][C:26]([CH:28]1[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(Br)C=C.[Cl-].[NH4+]>C1COCC1>[C:21]([O:25][C:26]([C:28]1([CH2:7][CH:5]=[CH2:6])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropyl amide was generated from 7.5 g (58.1 mmol) diisopropyl amine and 23.2 mL of 2.5 M n-butyl lithium in 200 mL THF at 0° C. under nitrogen. After stirring for 30 minutes at 0° C. the solution was taken to −78° C. where 7.5 g (52.8 mmol) of cyclopropanecarboxylic acid tert-butyl ester in 30 mL of THF was added dropwise over 5 min. After 4 h 12.8 g (106 mmol) of allyl bromide in 30 mL THF was added drop-wise over 10 min. to the clear golden solution. The reaction was allowed to slowly warm to room temperature. After 19 hours the reaction was poured into aqueous saturated ammonium chloride solution, extracted with ether, dried and concentrated to deliver an oil which was purified via Kugelrohr distillation (approx. 20 mm Hg; 60-75° C. oven) to deliver 5.4 g (56%) of the desired product as a clear colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1F)[C:25]#[N:26].C(OCC)(=O)C>CS(C)=O.O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]2[C:10]([C:11]([F:14])([F:12])[F:13])=[N:9]1)[C:25]#[N:26]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: FC(F)(F)c1n[nH]c2nccc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Compound (153a) (0.200 g), cesium carbonate (0.880 g), and 3-chloro-4-fluorobenzonitrile (0.154 g) were suspended in DMSO (50 mL), followed by stirring at 60° C. for 24 hr. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away to obtain 3-chloro-4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, which was used in the subsequent reaction without being purified. This 3-chloro-4-{4-chloro-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile, 4-(1-(hydroxymethyl)-1H-pyrazol-4-yl)-1H-imidazole hydrochloride (0.129 g), potassium carbonate (0.263 g), and copper(II) oxide (nanopowder) (0.020 g) were suspended in DMF (2.5 mL), followed by stirring at 120° C. for 24 hr. The reaction solution was diluted with ethyl acetate, and insoluble matters were filtered by celite. The solvent of the filtrate was distilled away, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (188) (0.012 g, 3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7](C(O)=O)=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13].[C:32]([OH:37])([CH2:35][CH3:36])([CH3:34])[CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[C@@H:4]([C:5]#[C:6][C:7]([O:37][C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:8])[C@H:3]1[C:12]([O:14][C@H:15]([C:29]#[N:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)=[O:13]
Reactant: CCC(C)(C)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
82 mg of 4-dimethylamino-pyridine were added with stirring at 5° C. to a mixture of 2.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-carboxycarbonyl-ethynyl]-cyclopropane-carboxylate, 12.5 ml of methylene chloride and 2.5 ml of tert.-amyl alcohol followed by the addition of 1.55 g of dicyclohexylcarbodiimide. The mixture was stirred at 20° C. for 41/2 hours and was cooled to 0° C. and filtered. The filtrate was evaporated to dryness under reduced pressure and was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.35 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-tert.-amyloxycarbonyl-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1>C(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:1]([Cl:4])=[O:2])[CH2:13][CH2:14]1
Reactant: O=C(Cl)Cl
Reactant: Clc1ccc(OC2CCN(Cc3ccccc3)CC2)cc1Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 16 g (0.16 mole) of phosgene in 200 ml of methylene chloride at 15° C. under nitrogen gas was added dropwise a solution of 47.2 g (0.14 mole) of 1-benzyl-4-(3,4-dichlorophenoxy)piperidine in 100 ml of methylene chloride. The addition was complete within 1 hr and stirring was continued for an additional hour. The mixture was concentrated on a rotary evaporator to give a light oil. The oil was dissolved in isopropyl either and the mixture filtered to remove a small amount of insoluble material. The filtrate was washed with 50 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The oil was triturated four times with 100 ml of hexane decanting off the hexane each time after cooling. The oil residue, 37 g (86%), was treated with 10 ml of triethylamine to quaternize (precipitate) any excess benzyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH:10]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:9][N:8]3[CH:7]=1)=O.[CH3:28][O:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34]([CH2:39][C:40]([NH2:42])=[O:41])=[CH:35][NH:36]2)=[CH:32][CH:31]=1>>[OH:19][CH2:18][CH:10]1[CH2:11][C:12]2[C:17]3=[C:16]([C:6]([CH:4]4[CH:39]([C:34]5[C:33]6[C:37](=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=6)[NH:36][CH:35]=5)[C:40](=[O:41])[NH:42][C:3]4=[O:2])=[CH:7][N:8]3[CH2:9]1)[CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc2c(CC(N)=O)c[nH]c2c1
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(CO[Si](C)(C)C(C)(C)C)C2
Product: COc1ccc2c(C3C(=O)NC(=O)C3c3cn4c5c(cccc35)CC(CO)C4)c[nH]c2c1

Procedure:
Beginning with (5-(tert-butyldimethylsilyloxymethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl]oxoacetic acid methyl ester and (6-methoxy-1H-indol-3-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([OH:23])=[O:22])([CH3:16])[CH3:15].[Cl-].[NH4+]>CN(C=O)C>[CH:14]([S:17][C:18](=[O:31])[CH2:19][C@H:20]([NH:24][C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:21]([O:23][CH2:2][C:3]#[N:4])=[O:22])([CH3:16])[CH3:15]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CC(=O)SC(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromoacetonitrile (0.510 ml, 7.32 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.153 ml, 0.878 mmol) were added to a solution of (S)-4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IB) (200 mg, 0.732 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (1 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-(isopropylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IB) (161 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([OH:9])[CH:8]=1)[NH2:5].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:5][C:4]1[CH:3]=[C:2]([OH:1])[CH:8]=[C:7]([OH:9])[CH:6]=1)=[O:21])[CH3:24]
Reactant: Nc1cc(O)cc(O)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1cc(O)cc(O)c1)C(=O)OCC
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A mixture of 3,5-dihydroxyaniline (2.0 g), 2-ethoxy-1,1-bis(ethoxycarbonyl)ethene (3.0 g) and ethanol (10 ml) was left to stand at room temperature for 2 days. The resulting solid was filtered off, dissolved in dimethylsulphoxide (20 ml) and then treated with water (100 ml). The resulting solid was washed with water, to give 1,1-bis(ethoxycarbonyl)-2-(3,5-dihydroxyphenylamino)ethene (3.2 g), m.p. 190°-192° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCOS(C)(=O)=O)ccc23)CC1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[7-(3-Methanesulfonyloxy-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 115, was dissolved in anhydrous dioxane together with piperazine (0.5 mmol) and the mixture was stirred at 100° C. overnight and then concentrated in vacuo, then diluted with water and extracted with DCM. The DCM extract was washed with water thrice, dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain 4-[7-(3-piperazin-1-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. This (0.05 mmol) was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.1 mmol) followed by methanesulfonyl chloride (0.1 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MEOH, neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), which was prepared as described in Example 66a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain 14.3 mg (45%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.13 (s, 1H), 8.04 (d, 1H), 7.35-7.22 (m, 4H), 6.88 (d, 2H), 6.33 (s, 1H), 4.31-4.13 (m, 4H), 3.89-3.80 (m, 4H), 3.74-3.56 (m, 3H), 3.20-3.03 (m, 6H), 2.61-2.38 (m, 11H), 2.22-1.88 (m, 6H). LC/MS (ESI): 638.1 (MH)+.
Reaction SMILES: O=[C:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=32)[C:4](=[O:18])[CH2:3]1.Br.Br[CH2:21][CH2:22][CH2:23][NH2:24].N1C(C)=CC=CC=1C>C(O)CCC>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:9]2[CH:10]3[N:5]([C:4](=[O:18])[C:3]4[CH2:21][CH2:22][CH2:23][NH:24][C:2]=4[CH2:11]3)[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: NCCCBr
Reactant: COc1ccc2c(c1)CCN1C(=O)CC(=O)CC21
Agent: Br
Solvent: CCCCO
Solvent: Cc1cccc(C)n1
Product: COc1ccc2c(c1)CCN1C(=O)C3=C(CC21)NCCC3
Temperature: 10 °C
Yield: 70.3 %

Procedure:
A solution of 27.3 Kg of 2,4-dioxo-9-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine, 19.6 Kg of 3-bromopropylamine hydrobromide and 22.8 Kg of 2,6-lutidine in 70 litres of n-butanol was refluxed for 1 hour. Butanol and excess 2,6-lutidine were removed under reduced pressure, and the solid residue dissolved in 150 litres of methanol at reflux temperature. The temperature was maintained above 70° C. while 150 litres of water was added. The mixture was cooled to 10° C., the precipitate filtered off and washed with 1:1 aqueous methanol. This product was recrystallized from a mixture of 150 Kg of methanol and 175 Kg of water. Drying under vacuum at 80° C. for three days gave 17.9 Kg of (±)-3-methoxy-5,6,9,10,11,12,13,13a-octahydroisoquino[2,1-g][1,6]naphthyridin-8-one, m.p. 202°-205° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)(C)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:35][CH2:34]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: COc1cccc(N2CCNCC2)c1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: CCO
Product: COc1cccc(N2CCN(CCCOc3cc4c5c(c(=O)oc4cc3OC)CCC5)CC2)c1
Yield: 58 %

Procedure:
Method B (60 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(3-methoxyphenyl)piperazine; yield 58%; fusion point 130°-132° C. (from ethanol and isopropanol). Fumarate: method E; yield 80%; fusion point 174°-175° C. (from acetone).
Reaction SMILES: [OH:1][C@H:2]([CH3:32])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[ClH:33]>ClCCl>[ClH:33].[CH3:24][NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH3:32])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:18][CH2:19]1
Reactant: C[C@@H](O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C(=O)OC(C)(C)C)CC4)c3c21
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (170 mg, 0.38 mmol, 1.0 equiv) in 5.5 mL of dichloromethane cooled to 0° C. Then hydrochloric acid (12 M, 0.5 mL) was added and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was concentrated under reduced pressure to give (2R)-1-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propan-2-ol hydrochloride (130 mg, crude) as a light yellow oil. The resulting hydrochloride (130 mg, crude) was dissolved in DMF (5 mL). Potassium carbonate (359 mg) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (125 mg) were added at room temperature and the resulting mixture was stirred for 14 h at 25° C. After completion of the reaction, the product was extracted with DCM, washed with brine and concentrated in vacuo. The crude product (160 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.1% HCOOH) and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254/220 nm. The product containing fractions were collected and evaporated to remove the water and CH3CN to give 2-[(4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (52.7 mg) as a white solid. MS (ES): m/z 473 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.46 (1H, s), 5.32-5.18 (1H, m), 3.94-3.92 (1H, m), 3.57 (2H, t), 3.45 (2H, t), 3.36 (3H, m), 3.08-3.10 (1H, m), 2.96-2.98 (1H, m), 2.67-2.62 (2H, m), 2.41-2.29 (6H, m), 2.070-1.97 (5H, m), 1.95-1.87 (2H, m), 1.64-1.52 (5H, m), 1.30 (3H, d).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br.C([O-])(O)=O.[Na+]>>[Br:14][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-methanesulfonylacetophenone (480 mg; 2.42 mmol) in 15 mL HOAC was added Br2 (2.42 mmol). The reaction was stirred overnight at r.t. The reaction mixture was carefully poured into NaHCO3 solution and extracted with EtOAC. The reaction yielded a light yellow solid which was used with no further purifiCation.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C[O-].[Li+].[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.O1CCCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]=[CH:10][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:18][N:16]=3)=[CH:12][CH:13]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ccc(F)cc2)nc1
Reactant: C#Cc1cccnc1N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccc(F)cc3)nc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
To a methanol (5.00 mL) solution of 2-(4-fluoro-phenoxymethyl)-5-(2-nitro-ethyl)pyridine (50.0 mg, 0.181 mmol) described in Manufacturing Example 72-1-3 was added lithium methoxide (13.7 mg, 0.362 mmol) under nitrogen atmosphere at room temperature, which was stirred for 30 minutes at room temperature. The solvent was evaporated from the reaction mixture under a reduced pressure, and anhydrous dichloromethane (4.00 ml) and anhydrous tetrahydrofuran (2.00 ml) were added to the residue. Titanium (IV) chloride (63.7 μL, 0.579 mmol) was added dropwise into the reaction mixture on a dry ice-ethanol bath (−78° C.), and stirred for 40 minutes at 0° C. Water and ethyl acetate were added to the reaction mixture on an ice bath (0° C.), and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain a crude product (43.0 mg). To a tetrahydrofuran (5.00 mL) solution of this crude product (23.0 mg) and 3-ethynyl-pyridin-2-ylamine described in Manufacturing Example 1-2-3 (3.44 mg, 0.029 mmol) was added triethylamine (12.2 μL, 0.083 mmol) at room temperature, which was stirred for 2 hours at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:2), the mixture was further purified by reverse-phase high-performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound (3.62 mg, 25.4%) as a ditrifluoracetic acid salt.