Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29]Cl)=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[C:25]2[N:26]([CH3:31])[C:27]([CH2:29][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[N:28][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Cn1c(CCl)nc2cccc(Cl)c21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(CCC#C[Si](C)(C)C)nc2cccc(Cl)c21
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of the trimethyl(prop-1-ynyl)silane (0.21 mL, 1.4 mmol) in THF (4 mL), was added at −78° C. nBuLi 2.5M in hexane (0.56 mL, 1.3 mmol). After 90 min at −78° C., a solution of 7-chloro-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (250 mg, 1.2 mmol) in THF (2 mL) was added. Mixture went from purple to orange and then dark brown. The reaction was quenched after 1 h at −78° C. with water and the solvent was evaporated to dryness to afford 338 mg of 7-chloro-1-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 100%) as a brown oily solid. It was carried through to the next step without purification.
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[C@H:7]([C:8]#[CH:9])[NH:6][C:5]1=[O:10])[CH3:3].[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH:2]([C@H:4]1[C@H:7]([CH:8]=[CH2:9])[NH:6][C:5]1=[O:10])[CH3:3]
Reactant: [H][H]
Reactant: C#C[C@@H]1NC(=O)[C@H]1C(C)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: C=C[C@@H]1NC(=O)[C@H]1C(C)O
Yield: 98.6 %

Procedure:
A solution of trans-3-(1-hydroxyethyl)-4-ethynyl-2-azetidinone (0.10 g) in ethanol (5 ml) is subjected to catalytic reduction with hydrogen gas in the presence of Lindlar catalyst (0.01 g). The reduction is continued until 14 ml of hydrogen gas has been absorbed. The catalyst is then filtered off and the filtrate is concentrated under reduced pressure to give 0.1 g of trans-3-(1-hydroxyethyl)-4-vinyl-2-azetidinone.
Reaction SMILES: [C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][NH:12][C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(=O)CC>[C:1]([C:9]1[C:10]([NH:15][C:16](=[O:19])[CH2:17][Cl:18])=[CH:11][N:12]([CH3:20])[C:13]=1[CH3:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc(NC(=O)CCl)c1C(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: Cc1c(C(=O)c2ccccc2)c(NC(=O)CCl)cn1C
Temperature: 25 °C

Procedure:
N-(4-benzoyl-5-methyl(1H)-pyrrol-3-yl)2-chloroacetamide (0.019 mole) was dissolved in butan-2-one (60 ml) and K2CO3 (4.5 g) and dimethylsulphate (0.037 mole) were added to the obtained solution. The reaction mixture was maintained at the reflux temperature for 5 hours and at room temperature overnight. An inert atmosphere was maintained throughout the process. The inorganic salts were filtered and the clear solution was evaporated under vacuum to yield a residue which upon crystallization from methanol gave the compound of the title.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=[O:43].[Li]CCCC>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:42]([C:38]2[N:37]([CH3:36])[CH:41]=[CH:40][N:39]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: Cn1ccnc1C=O
Agent: [Li]CCCC
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1-methyl-imidazole-2-carbaldehyde and n-BuLi
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]#[N:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:29](N)[CH2:30][NH2:31]>>[NH:17]1[CH2:29][CH2:30][N:31]=[C:16]1[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: N#Cc1cc2ccccc2n1-c1ccccc1
Reactant: NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1ccc(-n2c(C3=NCCN3)cc3ccccc32)cc1
Temperature: 200 °C

Procedure:
A stirred mixture of 1-phenyl-1H-indole-2-carbonitrile (15 g) and ethylenediamine monotosylate (17.6 g) was heated at 200° C. for 2 hours. After cooling, the reaction mixture was partitioned between toluene (100 ml) and dilute hydrochloric acid (400 ml). The aqueous layer was extracted with diethyl ether, cooled in an ice bath then basified with concentrated ammonia and reextracted with dichloromethane. The combined dichloromethane extracts were washed with water, dried and the solvent removed in vacuo. The residue was purified by chromatography on neutral alumina (grade III) eluting with 1% methanol in dichloromethane, followed by trituration with toluene to give 2-(2-imidazolin-2-yl)-1-phenyl-1H-indole as a white solid: yield 16.6 g (90%); mp 180.5°-182° C. The hydrochloride salt was prepared as described above: yield 16.3 g (95%); mp 263.5°-265.5° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][CH:25]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:25]([CH2:24][CH2:23][C:14]3[CH:15]=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=3[F:12])[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1ccc(C(F)(F)F)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (265.1 mg; 1.000 mmol) and 3-(2-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (220.2 mg; 1.000 mmol) afforded 3-ethyl-8-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([F:24])[C:10]([NH2:23])=[C:11]3[C:16]=2[O:15][CH2:14][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:12]3)=[C:5]([CH3:25])[O:4][N:3]=1.[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([F:24])[C:10]([NH2:23])=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:12]3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(F)c(N)c2c1OCC(c1cccnc1)=N2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(F)c(N)c2c1OCC(c1cccnc1)N2
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a solution of 8-(3,5-dimethylisoxazol-4-yl)-6-fluoro-3-pyridin-3-yl-2H-1,4-benzoxazin-5-amine (40 mg, 0.1 mmol) in ethanol (0.8 mL) and water (0.2 mL), sodium tetrahydroborate (4.5 mg, 0.12 mmol) was added and the mixture was heated at 90° C. for 15 minutes. Sodium tetrahydroborate (4.5 mg, 0.12 mmol) was added and the mixture was heated to 90° C. for 15 minutes again. The mixture was evaporated and extracted with ethyl acetate. The organic extracts were evaporated. Purification by preparative LCMS (pH 10) gave the desired compound 11 mg, 30%. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.50 (m, 1H), 7.80 (m, 1H), 7.40 (m, 1H), 6.35 (m, 1H), 5.61 (s, 1H), 4.78 (s, 2H), 4.60 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 2.20 (s, 3H), 2.01 (s, 3H). LCMS calculated for C18H18FN4O2 (M+H)+: m/z=341.1. found: 340.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[I:17]I>C1COCC1.CCCCCC.[Cl-].[Na+].O>[I:17][C:9]1[S:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: II
Reactant: COc1cccc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc2cc(I)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
In a 4 L mechanically stirred reactor, a solution of 1-benzothien-7-yl methyl ether (105 g, 0.64 mol) in anhydrous THF (2 L) is cooled down to −74° C. n-Butyl lithium in hexane is added (2.5 N, 285 mL, 0.71 mol) within 45 min, keeping temperature below −70° C. The mixture is stirred 30 min at −78° C. and a solution of iodine (179 g, 0.70 mol) in anhydrous THF (1 L) is added within 1 h, keeping temperature below −70° C. After addition, the mixture is allowed to come up to room temperature over 2 h and brine (500 mL) is added. The layers are roughly separated and the organic layer is partially evaporated. Additional brine (200 mL) is added to the residual aqueous layer (mixed with some THF). After decantation, the organic and aqueous layers are separated. The aqueous layer is extracted with ethyl acetate (500 mL). The organic layers are pooled, washed with aqueous sodium thiosulphate, dried (MgSO4) and the solvent evaporated in vacuo to give the crude iodo derivative (173.6 g, 93%) The solid is recrystallized from isopropanol (150 mL) to give pure compound (145.5 g, 88%); δH (600 MHz, CDCl3) 7.51 (s, 1H), 7.32 (d(br), J=7.89 Hz, 1H), 7.26 (t, J=7.89 Hz, 1H), 6.72 (d(br), J=7.89 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[C:5]([CH3:22])[CH:4]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>>[CH:26]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:22])=[N:10]1)([CH3:27])[CH3:25]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)c(C)c1
Yield: 39.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxy-2-methylphenyl)-7-(trifluoro-methyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.072 g) as a white solid.
Reaction SMILES: C[CH2:2][N:3](CC)[CH2:4]C.[CH3:8][N:9]1[C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20][C:21]3([CH2:26][CH2:25][N:24]([C:27]([C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31]([OH:33])=O)=[O:28])[CH2:23][CH2:22]3)[C:12]=2[CH:11]=[N:10]1.Cl.CNC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:2][N:3]([CH3:4])[C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=1[C:27]([N:24]1[CH2:25][CH2:26][C:21]2([C:12]3[CH:11]=[N:10][N:9]([CH3:8])[C:13]=3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[O:20]2)[CH2:22][CH2:23]1)=[O:28]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCN(C(=O)c2ccccc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccccc1C(=O)N1CCC2(CC1)Oc1ccccc1-c1c2cnn1C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
Et3N (170 μL, 1.2 mmol) was added to a mixture of 2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzoic acid (100 mg, 0.25 mmol), N-methylmethanamine hydrochloride (30 mg, 0.37 mmol), EDCI (48 mg, 0.25 mmol), and CH2Cl2 (1.5 mL) at ambient temperature. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 and was washed with 1N HCl. The layers were separated and the organic layer was washed with 1N NaOH, and then brine before it was dried over sodium sulfate and was concentrated in vacuo to give N,N-dimethyl-2-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzamide (38 mg) as a white solid. ESI-MS m/z calc. 430.2. found 431.3 (M+1)+; Retention time: 2.24 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=7.7 Hz, 1H), 7.45-7.37 (m, 3H), 7.46-7.22 (m, 2H), 7.30-7.21 (m, 1H), 7.13-7.00 (m, 2H), 4.52 (d, J=13.5 Hz, 1H), 4.19 (s, 3H), 3.74-3.51 (m, 2H), 3.31 (t, J=11.9 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.24-2.02 (m, J=13.9 Hz, 2H), 2.02-1.76 (m, 2H). N-isopropyl-4-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-ylcarbonyl)benzamide was synthesized from 4-(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-ylcarbonyl)benzoic acid using the procedures described above.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[N:15]4[N:16]=[C:17]([C:20]5[O:24][C:23]([CH2:25][N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:22][CH:21]=5)[CH:18]=[CH:19][C:14]4=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(-c2ccc3nnc(Cc4ccc5c(c4)CCO5)n3n2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1cc2c(cc1Cc1nnc3ccc(-c4ccc(CN5CCOCC5)o4)nn13)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
5-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-furan-2-carbaldehyde (21.6 mg, 0.06 mmol), morpholine (6.5 μL, 0.07 mmol) and AcOH (2 drops) were combined in DCM (1 mL). To this was added sodium triacetoxyborohydride (19 mg, 0.09 mmol) and the reaction was stirred at rt for 2 hours. The reaction was concentrated in vacuo followed by purification by HPLC (5-65% CH3CN over 35 min) resulting in the title compound (5.9 mg, 27%) as a solid. 1H-NMR (CD3OD/CDCl3): δ 8.23-8.21 (1H, d, J=9.6 Hz), 7.81-7.78 (1H, d, J=9.8 Hz), 7.42-7.41 (1H, d, J=3.5 Hz), 7.22 (1H, s), 7.17-7.15 (1H, d, J=9.6 Hz), 6.99-6.98 (1H, d, J=3.5 Hz), 6.67-6.65 (1H, d, J=8.3 Hz), 4.57 (2H, s), 4.45-4.38 (4H, m), 3.94 (4H, br s), 3.40-3.33 (4H, m), 3.17-3.13 (2H, t, J=8.8 Hz). ESI-MS (m/z): Calcd. For C23H23N5O3: 417.18; found: 418.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([C@H:14]3[O:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]5[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=5[N:31]=4)[CH2:16][CH2:15]3)=O)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:34][OH:35]>N1C=CC=CC=1>[OH:35][N:34]=[C:12]([C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)[C@H:14]1[O:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)[CH2:16][CH2:15]1
Reactant: NO
Reactant: COc1cccc2sc(C(=O)[C@@H]3CC[C@@H](NCc4ccc5c(n4)NC(=O)CS5)CO3)nc12
Agent: Cl
Solvent: c1ccncc1
Product: COc1cccc2sc(C(=NO)[C@@H]3CC[C@@H](NCc4ccc5c(n4)NC(=O)CS5)CO3)nc12
Yield: 20 %

Procedure:
A solution of (3R,6S)-6-{[6-(4-methoxy-benzothiazole-2-carbonyl)-tetrahydro-pyran-3-ylamino]-methyl}-4H-pyrido[3,2-b][1,4]thiazin-3-one (Example 29, 47 mg, 0.1 mmol), and hydroxylamine hydrochloride (5 eq) in pyridine (1 ml) was stirred at RT overnight. The mixture was concentrated in vacuo and partitioned between NH4OH and DCM. The organic layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (EtOAc/MeOH 9:1 +1% NH4OH) gave the title compound as yellow solid (10 mg, 20%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C=O)C.ClCCl.CO>[NH2:1][C:2]1[C:3]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCCCBr
Reactant: Nc1ncnc2pc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.3 %

Procedure:
7-Amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.25 g, 1.64 mmol, dried by coevaporation with dry DMF, 15 mL) was suspended in dry DMF to which sodium hydride (80 mg, 2 mmol, 60% dispersion in mineral oil) was added under argon atmosphere. The mixture was stirred at room temperature for 40 min and 1-bromopentane (0.25 mL, 2 mmol) was added. The reaction was continued for 3 h and the solvent was evaporated. The residue was coevaporated with toluene (25 mL). The solid thus obtained was dissolved in a mixture of dichloromethane and methanol (1:1, 10 mL) and impregnated onto silica gel (10 g). The solvents were evaporated under reduced pressure and the dry powder was loaded on a silica gel column (2×10 cm). The column was flash eluted with dichloromethane containing 0-5% methanol to yield 0.26 g (71%) of the title compound, mp 196-198° C. Ir (KBr): ν690 (=P-C), 1220 (-P=CH), and 3110 and 3280 (NH2) cm-1. Uv (MeOH): λmax266 nm (ε23,300). 31 p nmr (DMSO-d6): δ 62.57. 1H nmr (DMSO-d6): δ 0.83(t, 3 H, CH3), 1.25 (m, 4 H, 2CH2), 1.92 (m, 2 H, CH2), 4.27 (t, 2 H, NCH2), 8.37 and 8.67 (2s, 2 H, NH2), 8.60 (d, 1 H, C5H), and 9.03 (d, 1 H, J =54 Hz, C2H). Anal. Calcd. for C10H15N4P.0.5 CH2Cl2 : C, 47.63; H, 6.09; N, 21.17. Found: C, 47.47; H, 6.09; N, 21.86.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCCC1.C(O)(=O)C>C(Cl)Cl.CCOC(C)=O>[CH2:10]([O:9][C:1](=[O:8])[C:2](=[CH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20][CH2:21]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To a solution of diethyl malonate (710 μL, 4.7 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g,4.7 mmol) in methylene chloride (5 mL) was added piperidine (46 μL, 0.47 mmol) and acetic acid (27 μL, 0.47 mmol). The reaction mixture was stirred for 72 h at room temperature and then for 16 h at 45° C. EtOAc was added and the mixture was washed with water and brine, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (heptane/EtOAc, 3:1→1:3) to give 2-(1-tert-butoxycarbonyl-piperidin4-ylmethylene)-malonic acid diethyl ester (0.69 g 40%).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH3:9][C:3]([CH3:8])([CH:2]([NH:1][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)C(N)Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
To a solution of 251 g of methyl 3-amino-2,2-dimethyl-4-(p-methoxyphenyl)butyrate and 121 g of triethylamine in 750 ml of chloroform, there is added, with mechanical stirring and cooling with ice water, a solution of 210 g of p-toluenesulphonyl chloride in 500 ml of chloroform. After completion of the addition, which is carried out at such a rate that the temperature of the reaction mixture does not exceed 25° C., stirring is continued for 1.5 hours. Then the solution is washed with water, dilute hydrochloric acid and again with water, subsequently. After drying, the organic solvent is stripped off in vacuo. The residue is treated with ether, resulting in the crystallization of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7]Br.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: Clc1sccc1CBr
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1ccsc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Methylthiophene (19.63 g) was dissolved in acetonitrile (100 ml), and sulfuryl chloride (16.64 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, stirred under reflux for another 1 hour, then cooled to room temperature, and 10% aqueous sodium thiosulfate (200 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-3-methylthiophene (21.52 g). A mixture of 2-chloro-3-methylthiophene (3.53 g), N-bromosuccinimide (4.73 g), 2,2'-azobis(isobutyronitrile) (0.87 g) and carbon tetrachloride (25 ml) was stirred under reflux for 4 hours. The mixture was cooled to room temperature and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-bromomethylthiophene. A suspension of the crude product of 2-chloro-3-bromomethylthiophene and potassium acetate (9.82 g) in acetone (50 ml) was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-chlorothiophene. This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-hydroxymethyl-2-chlorothiophene (3.22 g). 3-Hydroxymethyl-2-chlorothiophene (3.16 g) was dissolved in methylene chloride (50 ml), and manganese dioxide (9.66 g) was added. The mixture was stirred at room temperature for 15 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-thiophenecarbaldehyde (3.16 g). The crude product of 2-chloro-3-thiophenecarbaldehyde was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.67 g) in water (10 ml) and 30% aqueous hydrogen peroxide (2.6 ml) were added. Further, sodium chlorite (3.41 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate to give 2-chloro-3-thiophenecarboxylic acid (1.92 g) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].S(Cl)(Cl)=O.[CH3:19]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1

Procedure:
Precursors of Example 28 starting from 4-chloro-3-methylsulfonylbenzoic acid via 4-N-hydrazino-3-methylsulfonylbenzoic acid (m.p. 243°-245° C.) and its hydrogenolytic N--N cleavage with Raney nickel catalyst in methanol/aq. NH3 under normal pressure at room temperature to give 4-amino-3-methylsulfonylbenzoic acid (m.p. 258°-262° C.) and subsequent reaction with thionyl chloride and methanol to give methyl 4-amino-3-methylsulfonylbenzoate (m.p. 146° C.).