Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14](C)=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1C)[CH:2]=[CH2:3].[OH:17][C:18]1C=CC(C#N)=CC=1OC>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][OH:12])=[NH:10])=[CH:7][C:6]=1[O:17][CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C)cc(C(=N)NO)cc1C
Reactant: COc1cc(C#N)ccc1O
Product: C=CCOc1ccc(C(=N)NO)cc1OC

Procedure:
The title compound is prepared in analogy to 4-allyloxy-N-hydroxy-3,5-dimethyl-benzamidine by allylating commercially available 4-hydroxy-3-methoxy-benzonitrile followed by transforming the nitrile to the hydroxyamidine; LC-MS: tR=0.59 min, [M+1]+=223.18.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(COCCc2ccc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3'RS,4'RS)-6-(2-benzyloxy-ethyl)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3'RS,4'RS)-6-(2-benzyloxy-ethyl)-3'-(naphthalen-2-ylmethoxy)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine in the form of a beige gum; MS: 453 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[N:26]([CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:25]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[C:24]([CH3:23])=[N:25][N:26]([CH2:39][C:40]([CH3:41])([OH:42])[CH3:43])[C:27]=3[CH3:38])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: Cc1nn(CC(C)(C)O)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(CC(C)(C)O)c3C)cc12

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (20.0 mg, 0.0521 mmol), 1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-2-methylpropan-2-ol (30.7 mg, 0.104 mmol), Pd(PPh3)4 (3.01 mg, 0.00261 mmol), K2CO3 (21.6 mg, 0.156 mmol) and 4:1 dioxane:water was microwaved at 100° C. for 45 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.23 (s, 3H), 1.24 (s, 3H), 1.80 (d, J=7.3 Hz, 3H), 2.07 (s, 3H), 2.17 (s, 3H), 3.65 (br. s., 3H), 4.01 (s, 2H), 5.06-5.15 (m, 1H), 6.89 (dd, J=9.1, 4.0 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H). MS (ES+): m/z=471.03/473.01 (100/50) [MH+]. HPLC: tR=3.47 min (polar—5 min, ZQ3).
Reaction SMILES: S(O[CH2:12][C:13]1([C:26]([O:28][CH3:29])=[O:27])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][NH2:41]>C(#N)C>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:40][NH:41][CH2:12][C:13]1([C:26]([O:28][CH3:29])=[O:27])[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14]1
Reactant: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC#N
Product: COC(=O)C1(CNCc2ccc(OC)cc2OC)CN(C(=O)OC(C)(C)C)CCO1
Reaction time: 15 h
Yield: 31.9 %

Procedure:
E4 (365 mg, 0.850 mmol) was dissolved in acetonitrile (10 mL), (2,4-dimethoxyphenyl)methanamine (700 μL, 4.66 mmol) was added and the solution was stirred for 15 h at reflux temperature. The reaction mixture was concentrated in vacuo, extracted with water/EtOAc and washed twice with water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography from toluene:EtOAc 100:0 to 20:80 which gave the title compound (115 mg, 32%). MS (ES) C21H32N2O7 requires: 424. found: 425.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25][C:26](OCC)=[O:27])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][O:4][C:3]3[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][OH:27])=[CH:24][C:2]=3[Cl:1])[CH2:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCc1ccc(OCCN2CCC(Cc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
The title compound was prepared from reduction of 1-[2-(2-chloro-4-ethoxycarbonylmethylphenoxy)ethyl]-4-(4-chlorobenzyl)piperidine (450.3 mg, 1.0 mmol) by LiAlH4 (38 mg, 1.0 mmol) as oily product (298 mg). 1H NMR (CD3OD) 1.248 (m, 2 H), 1.374 (s, 1 H), 1.572 (m, 4 H), 2.530 (m, 2 H), 2.677 (m, 1 H), 2.782 (m, 2 H), 2.991-3.139 (m, 4 H), 3.828 (m, 2 H), 4.131 (m, 2 H), 6.868 (m, 1 H), 7.103 (m, 2 H), 7.233 (m, 4 H). HRMS Calcd for C22H2735Cl2NO2 : 407.1435; Found: 407.1427.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[CH:7]=[CH:8][C:9]2[S:14]C=[CH:12][C:10]=2[CH:11]=1.C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:4][CH:3]=[CH:2][C:1]1[S:14][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=2[CH:12]=1
Reactant: c1ccc2sccc2c1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: CC=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
n-Butyl lithium (16.7 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (5.0 g, 37.3 mmol) in THF (80 mL) at -78° C. under a dry N2 atmosphere. After the addition wascompleted, the mixture was warmed up and stirred at 0° C. for 30 min. Allylbromide (16.1 mL, 186.5 mmol ) was added. After an additional 3.5 h., sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and dried. Silica gel (120 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent petroleum ether) to provide the title compound as an oil (3.74 g, 58%): NMR (CDCl3); δ 7.76 (d, J=9 Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.36-7.20 (m, 2H), 7.02 (s, 1H), 6.14-5.96 (m, 1H), 5.22 (dd, J=2, 17 Hz, 1H), 5.16 (dd, J=2, 17 Hz, 1H), 3.66 (d, J=8 Hz, 2H); MS (EI): [M+] 174 (100%); Anal. Calc. for C11H10S: C, 75.82, H, 5.78, N, 0.00. Found: C, 72.88, H, 5.56, N, 0.13.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31]1
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Reactant: OC1CCNCC1
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC(O)CC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Yield: 78.57 %

Procedure:
2α,3α-Epoxy-16β-(4-methyl-1-piperazinyl)-5α-androstane-17β-ol is reacted with 4-hydroxypiperidine as described in Example 3 to obtain the title compound in a yield of 78.57%, m.p.: 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])C(C#N)=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.Cl.[OH-].[Na+].[C:33]([OH:36])(=[O:35])[CH3:34]>O>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:34]([C:33]([OH:36])=[O:35])=[N:21]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Temperature: 120 °C
Yield: 78 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (31) (136 mg, 0.312 mmol) in glacial acetic acid (3.0 mL) was treated with concentrated hydrochloric acid (0.345 mL). The reaction mixture was heated to 120° C. for 24 h. Starting material was still present by LC/MS. Additional concentrated hydrochloric acid (0.34 mL) was added. The reaction mixture was heated to 120° C. for another 24 h. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). At this time, the reaction was made basic by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ether (100 mL). The organic layer was discarded. The aqueous layer was acidified by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (32) (111 mg, 78%) as an orange solid which was used without further purification; LRMS for C17H13Cl2N5O6 (M m/z=454. Molecular Weight=454.2291; Exact Mass=453.0243
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[O:10][C:9]2=[O:23])=[CH:4][CH:3]=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(N(CC)CC)C>O1CCCC1>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][C@@H:11]2[O:10][C:9](=[O:23])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])=[CH:3][CH:4]=3)[CH2:12]2)=[O:16])=[CH:21][CH:20]=1
Reactant: Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reactant: O=C(Cl)CCCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCCl)Nc1ccc(N2C[C@H](CNC(=O)c3ccc(Cl)s3)OC2=O)cc1

Procedure:
0.5 g (1.29 mmol) of N-{[(5S)-3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-5-chloro-2-thiophenecarboxamide (from Example 149) is dissolved in 27 ml of tetrahydrofuran and admixed with 0.2 g (1.29 mmol) of 5-chlorovaleryl chloride and 0.395 ml (2.83 mmol) of triethylamine. The mixture is concentrated under reduced pressure and chromatographed over silica gel using a toluene/ethyl acetate=1:1→ethyl acetate gradient. This gives 315 mg (52% of theory) of a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6](C)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]3[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:20][C:19]3=[O:35])[CH3:17])=[CH:12][CH:11]=2)=[N:3]1.Cl[C:37]1[CH:38]=CC(=O)N(C2CC2)N=1>>[CH:1]1([N:2]2[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][C:13]([C@@H:16]([N:18]4[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[O:20][C:19]4=[O:35])[CH3:17])=[CH:14][CH:15]=3)=[N:3]2)[CH2:38][CH2:37]1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Reactant: O=c1ccc(Cl)nn1C1CC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 3-{(S)-1-[4-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and 6-chloro-2-cyclopropylpyridazin-3(2H)-one following a procedure analogous to that described in Example 17. Mass spectrum (ESI+): m/z=488 [M+H]+
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][O:15]C)[CH2:6]2.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH2:6]2
Reactant: COCCN1Cc2cc(OC)ccc2C1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C1c2ccc(O)cc2CN1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
A mixture of 5-methoxy-2-(2-methoxy-ethyl)-2,3-dihydro-isoindol-1-one (150 mg, 0.68 mmol) and boron tribromide (1 M in CH2Cl2, 1.4 mL, 1.36 mmol) in CH2Cl2 (8 mL) at −78° C. was stirred for 16 h at RT. The mixture was then cooled to −78° C. and MeOH (25 mL) was added. After 1 h at −78° C. the mixture was evaporated and the residue purified by chromatography (SiO2, CH2Cl2:2N NH3-MeOH 98:2 to 90:10) to afford the title product (42 mg, 32%) as a light orange solid. MS m/e=193.3 (M+).
Reaction SMILES: [F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)=[NH:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(C(C)C)CC)(C)C.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>C(#N)C>[F:1][C:2]([F:34])([O:6][C:7]1[CH:33]=[CH:32][C:10]([CH:11]=[N:12][NH:13][C:14](=[NH:15])[N:16]([N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:21][CH:20]=2)[C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: CN(C)C(=O)Cl
Reactant: N=C(NN=Cc1ccc(OC(F)(F)C(F)F)cc1)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N(N=Cc1ccc(OC(F)(F)C(F)F)cc1)C(=N)NN=Cc1ccc(OC(F)(F)C(F)F)cc1
Yield: 92.9 %

Procedure:
A solution of 1,3-bis{[p-(1,1,2,2-tetrafluoroethoxy)benzylidene]amino}guanidine (29.84 g, 0.06 mol), diisopropylethylamine (15.51 g, 0.12 mol) and dimethylcarbamoyl chloride (129.2 g, 0.12 mol) in acetonitrile (200 mL) is stirred at reflux for 22 hours. The reaction mixture is cooled, and the acetonitrile is evaporated under reduced pressure. The residue is dissolved in ethyl acetate (250 mL), and the organic solution is washed with water, saturated NaCl and dried over Na2SO4. The solvent is evaporated under reduced pressure, and the residue is crystallized from benzene-hexanes to give the desired product as a yellow solid, mp 141.5°-143.5° C. in 92.9% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].[C:8]12([CH2:21][CH2:20][CH2:19][CH2:18]1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10](=[O:17])[CH2:9]2.C1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:10]1([OH:17])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:9]1
Reactant: O=C1CC2(CCCC2)c2ccccc21
Reactant: COCCCBr
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COCCCC1(O)CC2(CCCC2)c2ccccc21

Procedure:
The Grignard reagent is prepared from γ-methoxypropyl bromide (30.6 g; 0.2 moles) and magnesium flakes (4.8 g; 0.2 gram-atoms) in tetrahydrofuran and reacted with spiro(cyclopentane-1,1'-indane)-3'-one (18.6 g, 0.1 moles) in a manner analogous to example 1. The reaction product is shaken out with benzene, the combined benzene solutions are dried with anhydrous magnesium sulphate and the solvent is distilled off in vacuum. 3'-γ-methoxypropyl-spiro(cyclopentane-1,1'-indan)-3'-ol is obtained as a yellowish oil (yield 27.1 g). The crude methoxy compound is refluxed for 62 hours with 48% hydrobromic acid (50 ml) and acetic acid (100 ml). The solution is concentrated in vacuum, ether is added to the oil obtained, and then the solution is washed with water and 2 N sodium hydroxide solution. After drying with magnesium sulphate the solvent is distilled off and a brown oil is obtained, which essentially consists of 3'-γ-bromopropyl-spiro(cyclopentane-1,1'-indene). The compound can be purified by distillation in vacuum and is then obtained as a colourless oil of mp, 148° C./1 mm Hg. nD25 =1.5769.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[C:6]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>CN(C)C=O>[CH2:24]([O:23][C:6]1[C:7]2[N:12]([CH2:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:10]([Br:22])[C:8]=2[N:9]=[C:4]([N:3]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[N:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(OCc3ccccc3)c3c(n2)c(Br)cn3COCc2ccccc2)cc1

Procedure:
Sodium hydride (0.6 g, 50% dispersion) was added to a stirred solution of 2-amino-4-benzyloxy-5-N-benzyloxymethyl-7-bromopyrrolo[3,2-d]pyrimidine (1.2 g) in N,N-dimethylformamide (25 mL) followed by 4-methoxybenzyl chloride (1.1 mL). After 1 h the reaction was quenched carefully with water, chloroform was added and the solution was washed (×2) with water. Normal processing followed by chromatography afforded 4-benzyloxy-5-N-benzyloxymethyl-7-bromo-2-{N,N-bis-(4-methoxybenzyl)amino}pyrrolo[3,2-d]pyrimidine (1.7 g) as a white solid. 13C-NMR (CDCl3) δ 159.0, 158.5, 156.5, 151.5, 137.4, 137.0, 131.8, 131.6, 129.7, 128.9, 128.8, 128.4, 128.3, 128.0, 114.1, 110.5, 91.1, 77.8, 70.6, 68.0, 55.7, 49.4. Anal. calc. for C37H35BrN4O4: C,65.39; H, 5.19; Br, 11.76; N, 8.24. Found: C, 65.47; H, 5.17; Br, 11.55; N, 8.42.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-])=O.[C:14](N)(=[S:16])[CH3:15].O>S1(CCCC1)(=O)=O>[CH3:15][C:14]1[S:16][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N:1]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(N)=S
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Cc1nc2cc([N+](=O)[O-])ccc2s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 10.13 g of 2,4-dinitrochlorobenzene and 15 g of thioacetamide in 50 ml of sulpholane was heated to 100° C. and stirred at this temperature for 1 hour. After cooling, the mixture was clarified. 200 ml of water were added to the filtrate. The solid was filtered off with suction, washed with water and dried.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.8 %

Procedure:
A solution of acryloyl chloride (22.5 mg, 0.25 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 139, 108 mg, 0.25 mmol) in CH2Cl2 (12 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while being cooled by the bath, was then allowed to warm to r.t. and was then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3, brine and was then dried (MgSO4). Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (56 mg, 46%) as a brown solid after trituration with diethyl ether; 1H NMR: 1.75-1.82 (2H, m), 1.90-1.97 (2H, m), 2.08 (6H, s), 2.98-3.09 (3H, m), 3.54 (2H, t), 3.85 (3H, s), 3.93 (2H, t), 4.09 (2H, t), 5.69 (1H, dd), 6.18-6.25 (2H, m), 6.49 (1H, dd), 6.95 (1H, d), 7.70 (1H, s), 7.89 (1H, s), 8.03 (1H, s), 8.26 (1H, d), 9.24 (1H, s); m/z: ES+ MH+ 489.63.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1O
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 10 g of ethyl 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate and 50 ml of phosphorus oxychloride was heated at 60°C with stirring for 1 hour. The excess phosphorus oxychloride was removed under reduced pressure and the product was poured into ice-water. The insoluble matter was filtered off, the filtrate was adjusted to pH 8 by the addition of aqueous ammonia under cooling and extracted with ether. The extracts were dried over anhydrous magnesium sulfate. Then 0.5 g of activated carbon was added to the ether extracts for decoloration. The ether extracts were filtered, concentrated to a small volume and cooled. The precipitate was filtered to provide 8.6 g of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate as yellow needles, m.p. 99°-100°C (decomp.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[OH:4].[C:15](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[F:14][C:2]([F:1])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[O:4][CH3:15]
Reactant: N#Cc1cc(C(O)C(F)(F)F)ccn1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.8 %

Procedure:
To 4 ml of dimethylformamide were added 0.4 g of 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carbonitrile, 0.33 g of potassium carbonate and 0.34 g of methyl iodide, and the mixture was stirred at room temperature for 20 hours. Thereafter, an aqueous saturated ammonium chloride solution was added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.2 g of 4-(2,2,2-trifluoro-1-methoxyethyl)pyridine-2-carbonitrile.