Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4](=[CH:16][N:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])[N:18]=2)[C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C[C:28]([N:30](C)C)=O>[C-]#N.[C-]#N.[Zn+2].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>[Cl:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[N:17]1[CH:16]=[C:4]2[C:5]([NH:8][C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11][N:10]=3)=[N:6][CH:7]=[C:2]([C:28]#[N:30])[C:3]2=[N:18]1
Reactant: CC(=O)N(C)C
Reactant: Cc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(Nc2ncc(C#N)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 17 %

Procedure:
A suspension of [7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine (100 mg, 0.22 mmol), Zn(CN)2 (52 mg, 0.44 mmol), and Pd(PPh3)4 (25 mg, 0.022 mmol), in DMA (1.0 mL) was sealed in a microwave vial, purged with nitrogen, and irradiated in a microwave reactor at 150° C. for 30 minutes. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (0-70% ethyl acetate in cyclohexane), to afford the title compound as an off-white solid (15 mg, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br s, 1H), 9.36 (s, 1H), 8.80 (d, J=1.0 Hz, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.86 (d, J=1.0 Hz, 1H), 7.83 (s, 1H), 7.74 (dd, J=7.4, 1.8 Hz, 1H), 2.50 (s, 3H). LCMS (Method B): RT=3.84 min, m/z: 396 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH:12]([CH:13]=[CH:14][C:15]2[CH:16]=[C:17](C)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10][CH:9]1[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]#[N:30])=[O:23])=O)(C)(C)C.C(OC(N1C(C=CC2C=CC=CC=2)CCC1C(N1CCC[C@H]1C#N)=O)=O)(C)(C)C>>[C:15]1([CH2:14][CH2:13][CH:12]2[NH:8][C@H:9]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]#[N:30])=[O:23])[CH2:10][CH2:11]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(C=CC2CCC(C(=O)N3CCC[C@H]3C#N)N2C(=O)OC(C)(C)C)c1
Agent: CC(C)(C)OC(=O)N1C(C=Cc2ccccc2)CCC1C(=O)N1CCC[C@H]1C#N
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1CCC(CCc2ccccc2)N1

Procedure:
The title compound was synthesized by substituting 2-(2-(S)-cyano-pyrrolidine-1-carbonyl)-5-(R/S)-(2-m-tolyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in Example 36 with 2-(2-(S)-cyano-pyrrolidine-1-carbonyl)-5-(R/S)-(2-phenyl-vinyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H NMR (500 MHz, MeOH-d4) δ 1.83 (m, 1H), 1.99 (m, 2H), 2.26 (m, 6 H), 2.65 (m, 1H), 2.77 (m, 2H), 3.64 (dd, J=7.02, 6.39 Hz, 2H), 3.76 (m, 1H), 4.58 (t, J=8.26 Hz, 1H), 4.83 (dd, J=7.95, 4.52 Hz, 1H), 7.25 (m, 5H) ppm. MS (DCI) m/z 298 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:24]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (331 mg, 1.0 mmol) in acetone (10 mL) was added (bromomethyl)benzene (204 mg, 1.2 mmol) and K2CO3 (276 mg, 2.0 mmol). The mixture was stirred at RT for 16 hr. 50 mL of acetone was added and filtered. The filtrate was concentrated to afford 400 mg (95%) of 7-(2-aminophenyl)-2-(4-(benzyloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 421.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=1[O:39][CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][C:31]=3[O:39][CH3:40])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 65 %

Procedure:
Following the procedurre of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 2.7 g (0.01 mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl]ethanone and sodium carbonate in butanol, the title compound was prepared in 65% yield as white solid after recrystallization from isopropyl alcohol, m.p. 117.5°-118.5° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:41])[CH:17]([C:18]([O:20]CC2C=CC([N+]([O-])=O)=CC=2)=[O:19])[N:16]2[C:31](=[O:40])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[C:37]([CH3:39])[N:38]=3)[C@H:15]2[S:14]1>C(O)C.C(Cl)Cl.[Pd]>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:12][C:13]1([CH3:41])[CH:17]([C:18]([OH:20])=[O:19])[N:16]2[C:31](=[O:40])[CH:32]([NH:33][C:34]3[NH:35][CH:36]=[C:37]([CH3:39])[N:38]=3)[C@H:15]2[S:14]1
Reactant: Cc1c[nH]c(NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)(C)S[C@H]23)n1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1c[nH]c(NC2C(=O)N3C(C(=O)O)C(C)(C)S[C@H]23)n1
Reaction time: 3.5 h

Procedure:
A mixture of p-nitrobenzyl 2,2-dimethyl-6-(4-methylimidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate (200 mg.) and 10% w/w palladium-on-carbon in ethanol (12 ml.) and methylene chloride (3 ml.) was shaken under hydrogen at atmospheric pressure for 3.5 hours. The mixture was filtered, the filtrate evaporated to dryness and the residual gum triturated with ether to give 2,2-dimethyl-6-(4-methylimidazol-2-yl)aminopenam-3-carboxylic acid toluene-p-sulphonate as a yellow powder (118 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 1.5 (s, 3H); 1.6 (s, 3H); 2.11 (s, 3H); 2.3 (s, 3H); 4.35 (s, 1H); 5.40 (d, 1H); 5.62 (d, 1H); 6.72 (s, 1H); 7.1 (d, 2H); 7.5 (d, 2H); 8.76 (s, 1H). The sample was approximately 50% pure.
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:21]=1[N:20]=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[C:18]1[CH3:22])=[S+:13]2)[CH3:7].[CH2:23]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:38]=1[N:37]=[C:36]1[C:31]([CH:32]=[CH:33][CH:34]=[C:35]1[CH3:39])=[S+:30]2)[CH3:24].[CH2:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:55]=1[N:54]=[C:53]1[C:48]([CH:49]=[CH:50][CH:51]=[C:52]1[CH3:56])=[S+:47]2)[CH3:41].C(C1C=CC=[C:63]2[C:72]=1[N:71]=[C:70]1[C:65](C=CC=C1C)=[S+]2)C.C(Cl)(Cl)Cl>>[I-:2].[I-:2].[I-:2].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([N:37]2[CH2:36][CH2:31][CH2:29][CH2:38]2)[CH:9]=1)[CH3:7].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[C:44]([N:71]2[CH2:70][CH2:65][CH2:63][CH2:72]2)[CH:43]=1)[CH3:41].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:27]([N:20]2[CH2:19][CH2:14][CH2:12][CH2:21]2)[CH:26]=1)[CH3:24]
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cc(N2CCCC2)cc2[s+]c3cccc(C)c3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 9-ethyl-1-methylphenothiazin-5-ium tetraiodide hydrate (383 mg, 0.5 mmol) in anhydrous CHCl3 (20 mL) pyrrolidine (71 mg, 1.0 mmol) was added drop wise over 4 h. The resulting mixture was stirred at room temperature overnight and concentrated to dryness.
Reaction SMILES: C(OC([NH:8][C:9]([NH:24]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:24])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=1
Reactant: Cc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccnc(-c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yl)phenyl)guanidine (300 mg) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 6 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (119 mg).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7]C1C=C2C(C=CN2)=CC=1)(C)(C)C.[C:18]([O:22][C:23](=[O:40])[CH2:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29](N=C=O)=[CH:30][N:31]2[C:34](=[O:36])[NH2:35])=[CH:27][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C(N1C2C(=CC(OCCO)=CC=2)C(CC(O)=O)=C1)(=O)N>>[C:18]([O:22][C:23]([CH2:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:7][C:6]([OH:17])=[O:5])=[CH:30][N:31]2[C:34](=[O:36])[NH2:35])=[CH:27][CH:26]=1)=[O:40])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Cc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(N=C=O)cn(C(N)=O)c2c1
Agent: NC(=O)n1cc(CC(=O)O)c2cc(OCCO)ccc21
Product: CC(C)(C)OC(=O)Cc1ccc2c(CC(=O)O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yl)-acetic acid tert-butyl ester (described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-6-yl)-acetic acid tert-butyl ester) according to the protocol described scheme A9 steps A, B, D, E for the preparation of [1-carbamoyl-5-(2-hydroxy-ethoxy)-1H-indol-3-yl]-acetic acid. MS (LC/MS): 350.2/352.2 [M+NH4]+, 687.2/689.2 [2M+Na]+, 277.0/279.0 [MH−tBu]+, 288.0/290.0 [M−CONH2]−, 376.9/378.8 [M+HCOO]−, 662.8/664.7 [2M−H]−; tR (HPLC conditions f): 1.79 min.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:28])[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])C>CO>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[S:13][C:12]([NH:11][C:9](=[O:10])[NH:8][CH2:7][C:6]([OH:28])=[O:5])=[N:16][C:15]=2[CH3:17])=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NC(=O)NCC(=O)O)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous sodium hydroxide (2M, 0.5 ml) is added to a stirred solution of {3-[5-(4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-acetic acid ethyl ester (Example 60) (0.14 g, 0.00035 mmol) in methanol (2 ml). After stirring at room temperature for 18 hours the solvent is removed and dilute HCl is added. The resulting yellow solid is removed by filtration and recrystallised from ethanol to afford the title compound. MH+ 370.0
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([NH:27][NH2:28])[CH3:26].CC(O)C>O>[CH2:25]([N:27]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([F:24])[CH:21]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:28]1)[CH3:26]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: CCNN
Solvent: O
Solvent: CC(C)O
Product: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (400 mg), ethylhydrazine (369 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and 10% Pd—C (50% wet, 400 mg) was added. The mixture was stirred at room temperature for 1 h under H2 atmosphere, filtered and evaporated. The residue was suspended in AcOEt/IPE and collected by filtration to give the title compound (220 mg).
Reaction SMILES: C([Li])CCC.[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])#[CH:7].[CH:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][CH2:13][CH:12]([OH:21])[C:7]#[C:6][Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=CCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Following a modified procedure of Matsuda (Matsuda, F. Et al., Chem. Eur. J. 5, 3252-3259 (1999)); n-butyllithium (1.6 M in hexanes, 8.8 ml, 14.1 mmol, 1.0 eq.) was added dropwise to a solution of ethynyltrimethylsilane (2.0 ml, 14.1 mmol, 1.0 eq.) in THF (6 ml) at −78° C. After addition, the mixture was allowed to warm slowly to 0° C. and stirred for 1 h. The mixture was cooled to −78° C. and a solution of hydrocinnamaldehyde (2.2 ml, 17.0 mmol, 1.2 eq.) in THF (3 ml) was added dropwise. The mixture was then allowed to slowly warm to −10° C. and stirred for 1 h before being quenched by the addition of saturated NH4Cl solution (10 ml) followed by EtOAc (10 ml). The aqueous layer was extracted with EtOAc (3×10 ml), the combined organic phases were washed with brine (15 ml) before being dried (MgSO4), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/EtOAc (100:5), giving the title product 81 as a clear, colourless oil (3.1 g, 94%). Analytical data consistent with the literature (Matsuda, F. Et al., Chem. Eur. J. 5, 3252-3259 (1999)).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:19]2[CH:24]=[CH:23][N+:22]([CH3:25])=[CH:21][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[CH:8][C:7]([CH3:18])=[CH:6][CH:5]=2.[I-]>C(O)(=O)C.O=[Pt]=O>[CH3:1][C:2]1[N:3]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[CH:8][C:7]([CH3:18])=[CH:6][CH:5]=2
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2-c1cc[n+](C)cc1
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1CCN(C)CC1

Procedure:
4-[2,5-Dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1-methylpyridinium, iodide 8a (3.0 g) was dissolved in acetic acid (75 ml) and PtO2 (0.4 g) was added. After hydrogenation for 2 weeks at 3 ato the catalyst was filtered off, the acetic acid was evaporated in vacuo and water (50 ml) was added. The thus obtained acidic solution was made alkaline (pH>9) with concentrated sodium hydroxide and extracted with ethyl acetate (2×50 ml). The organic phases were successively washed with diluted sodium hydroxide (50 ml), washed with brine and dried (Na2SO4). Evaporation of the solvent gave 1.3 g of the title compound as an oil, which was purified by column chromatography on silica gel (eluted with ethyl acetate/ethanol 8:1 containing 4% triethylamine) and crystallized from heptane. Yield 0.4 g, mp 110°-112° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])C>C(O)C>[O:11]1[CH2:10][CH2:9][C:8]([C:6]([OH:7])=[O:5])([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
6M potassium hydroxide solution (10 mL, 60 mmol) was added to an ice-cooled solution of tetrahydropyran-4,4-dicarboxylic acid diethyl ester (5 g, 21.7 mmol) in ethanol (40 mL) and heated at reflux for overnight. The volatiles were evaporated, the residue diluted with water and acidified with conc. hydrochloric acid. The mixture was allowed to stand overnight then extracted with ether (3×25 mL). The combined ether layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford tetrahydro-pyran-4,4-dicarboxylic acid (2.3 g, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[I:22]I>CO.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][I:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1Cc2c(C#CI)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.72 g (10 mmol) of 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 30 ml of methanol and cooled to 10°. There were then added simultaneously thereto in portions within about 10 minutes 5 ml of 28% sodium hydroxide solution and 3 g of iodine. After stirring at room temperature for 1 hour the suspension was diluted with about 30 ml of water, suction filtered and the suction filter cake was dried. By two recrystallizations from methylene chloride and ethyl acetate and from dioxane there was obtained 7-chloro-4,5-dihydro-3-(2-iodoethynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 215°-216°.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:13][C:14]([CH3:40])([CH3:39])[CH:15](O)[CH2:16][C:17]1[N:18]([CH2:35][CH2:36][CH3:37])[C:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:23]=2)=[CH:20][N:21]=1.N12CCCN=C1CCCCC2>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:13][C:14]([CH3:39])([CH3:40])[CH:15]=[CH:16][C:17]1[N:18]([CH2:35][CH2:36][CH3:37])[C:19]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:23]=2)=[CH:20][N:21]=1
Reactant: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CC(O)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=CC(C)(C)C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
Triethylamine (0.74 ml, 5.05 mmol), followed by methane sulphonyl chloride (0.103 ml, 1.33 mmol) was added to a stirred solution of 4-[2-(3,3-dimethyl-2-hydroxybut-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine (Method 101; 480 mg, 1.26 mmol) in DCM (40 ml) at ambient temperature and the mixture stirred for 24 hours. The volatiles were removed by evaporation and toluene (10 ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 ml, 2.54 mmol) was added to the residue. The mixture was heated at reflux for 5 hours, allowed to cool, washed with water and extracted with EtOAc. The extracts were combined, dried and the solvent removed by evaporation to give the title compound (240 mg, 53%). NMR: 0.64 (t, 3H), 1.15 (s, 9H), 1.53 (q, 2H), 4.64 (t, 2H), 6.38 (d, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (d, 3H), 7.75 (s, 1H), 8.38 (d, 1H), 9.38 (s, 1H); m/z 362.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][O:11]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]([CH2:19][O:20][CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)[CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CO)COCC1COC(C)(C)O1
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To a solution of crude [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 3.06 mmol) in MeOH (10 mL) was added Pd/C (300 mg). The mixture was transferred to an autoclave reactor, charged with 55 psi of hydrogen, and stirred. After 1.5 h, LCMS analysis indicated the completion of the reaction. The reaction mixture was then filtered through celite and concentrated under reduced pressure to give [1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-2-hydroxy-ethyl]-methyl-carbamic acid tert-butyl ester (0.875 g, 95%), which was used without purification. LRMS (M−Boc+H+) m/z 220.2.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCc2ccccn2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=397.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH3:34]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([F:25])=[C:27]([CH3:34])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1cc(CBr)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Cc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)ccc1F
Yield: 1.9 %

Procedure:
The title compound (0.002 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 4-fluoro-3-methylbenzyl bromide (0.09 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C21H21ClFN3, 369.14; found, m/z 370.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.47 (m, 2H), 7.45-7.42 (m, 2H), 7.07-7.01 (m, 1H), 7.00-6.95 (m, 1H), 6.95-6.90 (m, 1H), 5.31 (s, 2H), 2.97-2.91 (m, 4H), 2.89-2.84 (m, 2H), 2.82-2.77 (m, 2H), 2.22 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([O:15]C(=O)C)[C@H:11]([CH3:19])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@@H:12]([OH:15])[C@H:11]([CH3:19])[O:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)O[C@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H]1O[C@H](O[Si](C)(C)C(C)(C)C)CC[C@H]1O
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of the acetate from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), at room temperature, was added 1N NaOH (0.14 ml, 1.1 eq.) and the solution was stirred for 45 minutes. It was then poured in H2O and the aqueous phase was extracted 3× with CH2Cl2. The combined organic extracts were dried over MgSO4, the solids were filtered and the solvent evaporated to give 30 mg (96%) of the pure titled alcohol.