Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[N:11]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]=1)=O>O1CCCC1.CO>[OH:30][CH:23]([C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])=[N:11][C:7]([CH2:5][OH:4])=[N:8]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)Cc1nc(CO)nn1-c1ccc(Cl)cc1C(O)c1ccccc1
Temperature: 0 °C

Procedure:
9.1 g (0.24 mole) of sodium borohydride is added portionwise at room temperature, with stirring, to a solution of 16.0 g (0.040 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 2] in 320 ml of tetrahydrofuran and 320 ml of methanol. The temperature of the reaction solution rises during the addition to 40°. The reaction mixture is subsequently heated for one hour at 50°; 100 ml of ice water is then added, and the bulk of the tetrahydrofuran and of the methanol is evaporated off in vacuo. The aqueous residue is extracted twice with ethyl acetate. The organic phase is washed once with 1 N sodium hydroxide solution, and is then extracted three times with 2 N hydrochloric acid solution. Sodium carbonate is added to the aqueous acidified extracts until the pH-value reaches 10. The precipitated base is dissolved in ethyl acetate; the solution is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether and hexane, whereupon the reaction product precipitates in crystalline form. After filtration with suction and drying in vacuum, there is obtained 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-methanol, m.p. 121°-123°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C@H:14]([OH:17])[C:13]2=[O:18])[CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][C:7]2=[O:11].[Br:19][C:20]1[CH:25]=[C:24](O)[CH:23]=[CH:22][N:21]=1>>[Br:19][C:20]1[CH:25]=[C:24]([O:17][C@@H:14]2[CH2:15][CH2:16][N:12]([C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([F:1])[CH:3]=3)[CH2:9][CH2:8][C:7]4=[O:11])[C:13]2=[O:18])[CH:23]=[CH:22][N:21]=1
Reactant: O=C1CCc2c(F)cc(N3CC[C@H](O)C3=O)cc21
Reactant: Oc1ccnc(Br)c1
Product: O=C1CCc2c(F)cc(N3CC[C@@H](Oc4ccnc(Br)c4)C3=O)cc21

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-1-(7-fluoro-3-oxo-indan-5-yl)-3-hydroxy-pyrrolidin-2-one with 2-bromo-pyridin-4-ol provided the title compound. MS ESI+: m/z=405 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CO>[N:13]([CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of the commercially available 4-bromoacetyl-benzonitrile (5 g, 22.32 mmol) in 150 mL of methanol was added sodium azide (1.74 g, 26.78 mmol) and the contents stirred at room temperature for 2 h. After removal of the solvent, the residue was treated with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated to give a yellow solid (3.90 g, 94%). This compound was used for the next step without any further purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].C(N(CC)CC)C.[O:11]1[CH:16]2[CH:12]1[C:13](=O)[CH2:14][C:15]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[O:17][Si](C)(C)C.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:13]1[C:12](=[O:11])[CH2:16][C:15]([OH:17])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:14]=1
Reactant: CCCCCCCCC1(O[Si](C)(C)C)CC(=O)C2OC21
Reactant: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1

Procedure:
A solution of 910 mg of sodium thiomethoxide dissolved in 100 ml of methanol was stirred under ice-cooling and stirring for 15 minutes. Triethylamine (6 ml) was added, and after the mixture was stirred for 10 minutes, a solution of the above crude oil of 2,3-epoxy-4-octyl-4-trimethylsilyloxycyclopentanone in 15 ml of methanol was added dropwise. After the mixture was stirred for 6 hours, the reaction mixture was poured onto saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude oil of 2-methylthio-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[ClH:20].N([O-])=O.[Na+].[Na+].[Cl-]>S([O-])([O-])(=O)=O.[Cu+2].O>[Cl:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5]
Reactant: CC(O)(CCCl)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Cl
Agent: [Cu+2]
Agent: O=N[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(O)(CCCl)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
2.78 g. of 1-chloro-3-(4'-amino-4-biphenylyl)-butan-3-ol are dissolved in 30 ml. of 10% hydrochloric acid, a solution of 0.7 g. of NaNO2 in 2 ml. of water is added at 0°-5°, the resulting diazonium salt solution is added slowly dropwise to a hot solution of Cu2Cl2 (obtained by passing SO2 into a hot solution of 2.1 g. of copper sulfate and 2.6 g. of NaCl in 13 ml. of water) and the mixture is heated to 90°-95° for a further 30 minutes, cooled and worked up in the customary manner to give 1-chloro-3-(4'-chloro-4-biphenylyl)-butan-3-ol, m.p. 98° - 100°.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C:13](=[CH:14][C:15](=[O:38])[C@@H:16]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@H:21]([CH3:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12]1)(=O)C.N#N>CO>[OH:10][C@H:11]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C:13](=[CH:14][C:15](=[O:38])[C@@H:16]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@H:21]([CH3:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a suspension of finely ground K2CO3 (3.45 g , 25 mmoles) in 250 ml of methanol was added methyl 3β-acetoxy-7-oxochol-5-en-24-oate (1) (11.1 g, 25 mmoles). After stirring at 450° for 15 min in a N2 atmosphere, most of the methanol was removed in vacuo from the clear brown reaction mixture. The residue was suspended in H2O and extracted three times with CH2Cl2. The combined extracts were washed with H2O twice and saturated brine and dried with MgSO4. Evaporation in vacuo gave 10.1 g of nearly pure 2 as a pale yellow solid. The nuclear magnetic resonance data for this and subsequent Examples was taken at 400 MHz in CDCl3 : δ 0.68 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.21 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.70 (s, 1H, 6-H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:29]([SnH:33]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32]>>[CH2:15]([Si:3]([CH2:13][CH3:14])([CH2:1][CH3:2])[O:4][C:5]([CH3:12])([CH2:9][CH2:10][CH3:11])[CH2:6]/[CH:7]=[CH:8]/[Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:16]
Reactant: C#CCC(C)(CCC)O[Si](CC)(CC)CC
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/CC(C)(CCC)O[Si](CC)(CC)CC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
A solution of 40.0 g of 4-triethylsilyloxy-4-methyl-1-heptyne, 180 mg of azobisisobutyronitrile, and 50 ml of tri-n-butyltin hydride is stirred under an argon atmosphere at 130° C. for 2 hours, then allowed to cool to ambient temperature. The excess tin hydride is removed by distillation and the residue purified to provide 63.5 g of the (E)-4-triethylsilyloxy-4-methyl-1-tri-n-butylstannyl-1-heptene (b.p. 160°-88° C. at 0.6 mm).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][O:38]C3CCCCO3)[CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH2:37][OH:38])[CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:46])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M281) (0.34 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (152 mg, 64%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[O:43]1CC[C@H:45](O)[CH2:44]1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([C@@H:14]3[CH2:45][CH2:44][O:43][CH2:15]3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O[C@H]1CCOC1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn([C@@H]3CCOC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-tetrahydrofuran-3-ol and isolated as colorless gum. MS(m/e): 353.3 (MH+).
Reaction SMILES: [ClH:1].C([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(OCC1C=CC=CC=1)=O.[H][H].CCOCC>CO.[C].[Pd]>[ClH:1].[NH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][C:28]1[CH:37]=[C:36]2[C:31]([C:32]([CH3:39])=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1)=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: [H][H]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)OCc3ccccc3)ccc12
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CN)ccc12
Yield: 94.1 %

Procedure:
7-(Nα -carbobenzoxyglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (559 mg, 1 mM) was dissolved in methyl alcohol (50 ml) and palladium-carbon catalyst (50 mg) was added thereto. This mixture was stirred while being treated with hydrogen gas for 3 hours. The catalyst was removed by filtration and the thus obtained filtrate was concentrated to yield solid material. To the residue ether (50 ml) was added to yield a powder. The powder was separated by filtration and dried to give 7-(glycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [II] (400 mg).
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[C:7]3([O:22][CH2:23][CH2:24][C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][CH2:8]3.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1CCCN(C)C1=O.[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br>O1CCCC1>[F:44][C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47][CH:14]([CH2:13][N:10]1[CH2:11][CH2:12][C:7]2([C:5]3[S:6][C:2]([F:1])=[CH:3][C:4]=3[CH2:24][CH2:23][O:22]2)[CH2:8][CH2:9]1)[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)CCN1CCC2(CC1)OCCc1cc(F)sc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1F)CN1CCC2(CC1)OCCc1cc(F)sc12
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of tert-butyl 3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)propanoate (4.9 g, 13.78 mmol) in tetrahydrofuran (41 mL) under N2 and cooled to −78° C., lithium bis(trimethylsilyl)amide 1M (41.35 mL, 41.45 mmol) is added dropwise. The resulting mixture is stirred at that temperature for 3 hours. Then, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.33 mL, 11.03 mmol) is added, and the resulting solution is stirred at the same temperature for 30 min. To the resulting mixture, 2-fluorobenzyl bromide (2.33 mL, 19.3 mmol) in dry tetrahydrofuran (1 mL) is added and stirring is continued. The temperature is allowed to go from −78° C. to room temperature overnight. The crude reaction mixture is quenched with aqueous saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer is decanted, dried over magnesium sulfate, the solvent is evaporated and the crude obtained is purified by normal phase Isco chromatography using ethyl acetate/hexane from 5/95 to 20/80 to yield 5.06 g of the title compound obtained as colorless oil. MS (m/z): 464 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:24]1[C:25]([O:51][CH3:52])=[C:26]([C:38]#[C:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][CH:41]=2)[CH:27]=[C:28]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[CH:29]=1)([CH3:23])([CH3:22])[CH3:21].C[Si](C)(C)[Si](C)(C)C>C([Pd]Cl)C=C.O>[C:20]([C:24]1[C:25]([O:51][CH3:52])=[C:26]([CH:27]=[C:28]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[CH:29]=1)/[CH:38]=[CH:39]/[C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:48])=[O:49])=[CH:42][CH:41]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1c(C#Cc2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: C=CC[Pd]Cl
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 81 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a flask was added allylpalladium(II) chloride (0.98 g; 2.67 mmol) and triphenyl phosphine (2.8 g; 10.69 mmol). Vacuum and nitrogen purged. Sparged dimethylacetamide (50 ml) (nitrogen bubbled) was added and the solution was mixed at room temperature for 2 hrs. N-(4-((3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl)-2-methoxyphenyl)ethynyl)phenyl)methanesulfonamide (6) (50 g; 107 mmol) was dissolved in 100 mL of nitrogen sparged dimethylacetamide in a separate flask. This was inerted with nitrogen after the dissolution. The catalyst solution was transferred to the second flask containing substrate (6). Water (5 ml) and 1,1,1,2,2,2-hexamethyldisilane (16.1 mL; 160 mmol) were then added to the reaction mixture. The mixture was heated to 81° C. for total of 18 hours. The reaction mixture was cooled to ambient temperature and quenched with 500 ml THF and 500 ml of a solution of 7% NaCl, 2.5% NaHCO3 and 1% of cysteine. The quenched mixture was stirred for 1 hour and filtered to remove particulates. The filtrate was separated. The aqueous layer was back extracted with 250 mL THF and the combined organic layers washed again with 250 ml of a solution of solution of 7% NaCl, 2.5% NaHCO3 and 1% of cysteine. The organics were treated with activated carbon and the filtrate concentrated and solvent switched to 500 ml of methanol. The slurry was mixed at 50° C. for 60 minutes, cooled to ambient overnight. The slurry was filtered, and the solids washed with methanol, and dried to give 43.86 grams of the titled compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (s, 9 H) 2.99 (s, 3 H) 3.76 (s, 3 H) 5.62 (d, J=7.82 Hz, 1 H) 7.12-7.29 (m, 5 H) 7.51-7.65 (m, 3 H) 7.72 (d, J=7.82 Hz, 1 H) 9.83 (s, 1 H) 11.39 (s, 1 H) MS (APCI) m/z 470.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:21]2)[N:13]=3)[CH:7]=[CH:6][C:3]=1[CH2:4][N:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1C=O
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)ccc1CN1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (22.6 mg, 61 μmol), azetidine-3-carboxylic acid (31 mg, 305 μmol), and acetic acid (28 μL, 488 μmol) in 1:1 CH2Cl2/MeOH (2.0 mL) was stirred at 25° C. for 1 h. Sodium cyanoborohydride (6.9 mg, 110 μmol) was then added, and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo, dissolved in 2 mL DMSO+20 μL trifluoroacetic acid, filtered, and purified by rpHPLC (10-100% acetonitrile/water+0.1% TFA) to provide 1-((2-methyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)methyl)-azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][C:16]#[N:17])=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].[NH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:4]2[C:3]=1[CH:15]=[C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)[N:17]=[C:5]2[OH:6]
Reactant: COc1cc(C(=O)O)c(CC#N)c(Cl)c1OC
Reactant: Cc1cc(N)n[nH]1
Solvent: CC(=O)O
Product: COc1cc2c(O)nc(Nc3cc(C)[nH]n3)cc2c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 3-Chloro-2-cyanomethyl-4,5-dimethoxy-benzoic acid, 3-amino-5-methylpyrazol and acetic acid to give 5-Chloro-6,7-dimethoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol. LC-MS: m/e 335 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:6].[OH-].[Na+]>O.C(OCC)C>[CH:4]1([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(CCCBr)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Temperature: 25 °C

Procedure:
A stirred mixture of 4-bromo-2'-nitrobutyrophenone (3.44 g, 0.013 mole) and NaOH (0.76 g, 0.019 mole) in water is heated at reflux temperature until reaction is complete by TLC, cooled to room temperature and extracted with diethyl ether. The ether extracts are combined, dried over Na2SO4 and concentrated in vacuo to give a dark brown liquid residue. The residue is taken up in diethyl ether, filtered through silica gel and concentrated in vacuo to give the title product as a yellow oil, identified by 1HNMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N=C(N)c1cccc(F)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2cccc(F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=362.9 (M+H+), was prepared from 3-fluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [F:1][C:2]1[C:13]([I:14])=[CH:12][C:5]([CH2:6]OS(C)(=O)=O)=[C:4]([CH2:15]OS(C)(=O)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30]1([CH:36]([NH2:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH:36]([N:43]1[CH2:15][C:4]2[C:5](=[CH:12][C:13]([I:14])=[C:2]([F:1])[CH:3]=2)[CH2:6]1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)OCc1cc(F)c(I)cc1COS(C)(=O)=O
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Yield: 55 %

Procedure:
To a mixture of 5.93 mmol methanesulfonic acid 4-fluoro-5-iodo-2-methanesulfonyloxymethyl-benzyl ester and 14.8 mmol N,N-diisopropylethylamine in 7 ml DMF at 0° C. was added dropwise a solution of 6.53 mmol diphenylmethylamine in 5 ml DMF. The mixture was heated at 60° C. for 16 h and was then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: ethyl acetate/heptane) to afford the title compound as a light yellow solid (55% yield).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:24]2[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ncc(F)cn1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncc(F)cn1
Yield: 1 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(5-fluoropyrimidin-2-yl)but-3-yn-2-ol to give the titled compound as a brown solid (3.5 mg, 1%).
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])([CH3:14])[CH2:6][C@:7]1([C:10]([F:13])([F:12])[F:11])[CH2:9][O:8]1.Cl([O-])=[O:24].[Na+].S(=O)(=O)(O)N>[Cl-].[Na+].O>[CH3:14][C:5]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]([OH:24])=[O:18])([CH3:4])[CH2:6][C@:7]1([C:10]([F:12])([F:13])[F:11])[CH2:9][O:8]1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C=O
Agent: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred, ice-cooled, acetonitrile (250 mL) solution of 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzaldehyde (20 g, 73.5 mmol) was added a solution of sodium chlorite (7.4 g, 73.5 mmol in 100 mL water) followed immediately by a solution of sulfamic acid (7.13 g, 73.5 mmol in 100 mL water). After 30 minutes, the ice-cooled reaction mixture was treated with 500 mL of brine and extracted with three 300 mL portions of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated in vacuo to give 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]benzoic acid as a colorless thick oil (18 g, 85%).