Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=O)=[CH:5][CH:4]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[N:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2ccnc2C=O)cc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-(4-methoxyphenyl)-1H-imidazole-2-carbaldehyde (200 mg, 1 mmol), (R)-2-methylpropane-2-sulfinamide (145 mg, 1.2 mmol), and CuSO4 (160 mg, 1 mmol) were combined in DCM (5 mL). The reaction was stirred at ambient temperature for 15 hr. The reaction was filtered, solvents removed in vacuo, and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 305.9 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[N:26][OH:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:27])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[N:26][OH:27])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: ON=C(Cc1ccccc1)c1cccnc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
A solution of 7.7 g of p-toluenesulfonyl chloride in 15 ml of pyridine is added dropwise in the course of 5 minutes to a solution, which is stirred at -10°, of 8.5 g of benzyl 3-pyridyl ketone oxime in 20 ml of pyridine. The reaction mixture is placed in a refrigerator for 24 hours and then poured onto ice/water. After some stirring and grinding, the oil which has separated out solidifies to crystals. These are filtered off with suction, washed with water and dried under a high vacuum. Benzyl 3-pyridyl ketone oxime p-toluenesulfonate is obtained and this is employed in the next stage without further purification.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1O[CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[OH:10]>>[CH3:2][C:3]1[CH:4]([OH:10])[C:5](=[O:6])[CH:7]=[CH:8][N:1]=1
Reactant: N
Reactant: Cc1occc(=O)c1O
Product: CC1=NC=CC(=O)C1O

Procedure:
An ammonia solution is added to a solution of maltol dissolved in hot distilled water. The pH of this solution is adjusted to 9.8 by the addition of HCl solution. The mixture is kept under reflux overnight and then decolorized with activated charcoal. The solvent is removed under reduced pressure. The white product is obtained upon recrystallization from hot water.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[C:20](Br)[C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].O1CCOCC1.CB1OB(C)OB(C)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:1][C:2]1[CH:21]=[C:20]([CH3:23])[C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: CC1(C)Oc2cc(N)cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Yield: 88.6 %

Procedure:
A mixture of 7-amino-5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(7); 140 mg), potassium carbonate (159 mg), dioxane (11 mL), trimethylboroxin (134 μL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31 mg) was refluxed under argon atmosphere for 2 hours. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=3/1→3/7) to give 7-amino-4-(4-fluorophenyl)-2,2,5-trimethyl-2H-1,4-benzoxazin-3(4H)-one (102 mg) as a pale yellow powder.
Reaction SMILES: S1C=CC=C1[Cl:6].[CH3:7][O:8][CH2:9][CH2:10][N:11]1[C:19]([C:20]([OH:22])=O)=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[N:12]1>C1(C)C=CC=CC=1>[CH3:7][O:8][CH2:9][CH2:10][N:11]1[C:19]([C:20]([Cl:6])=[O:22])=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]2)=[N:12]1
Reactant: Clc1cccs1
Reactant: COCCn1nc2ccccc2c1C(=O)O
Solvent: Cc1ccccc1
Product: COCCn1nc2ccccc2c1C(=O)Cl
Yield: 102.1 %

Procedure:
Thienyl chloride (2.6 ml; 0.036 mol) was added to a suspension of 2-(2-methoxyethyl)-2H-indazole-3-carboxylic acid (3.6 g; 0.016 mol) in toluene (100 ml) and the reaction mixture was heated under reflux for 24 h. The solvent was removed by evaporation at reduced pressure and the residue was taken up twice in n-hexane. 3.9 g of 2-(2-methoxyethyl)-2H-indazole-3-carbonyl chloride was thus obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH3:33])=[CH:4][C:5]([O:29][CH:30]([CH3:32])[CH3:31])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH:46]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:30]([O:29][C:5]1[CH:4]=[C:3]([CH3:33])[C:2]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[CH:46]=2)=[CH:7][C:6]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[C:12]([CH3:28])=[CH:11][N:10]=1)([CH3:32])[CH3:31]
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1Br
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1-c1cnn(CCN2CCOCC2)c1
Temperature: 150 °C

Procedure:
A mixture of N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (53 mg, 0.099 mmol), 4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-morpholine (Boron Molecular, 61 mg 0.20 mmol), K3PO4 (58 mg), Pd2(dba)3 (10 mg), and tricyclohexylphosphine (8 mg) in 1 mL of 1,4-dioxane/H2O (3/1 v/v) is heated in a sealed tube at 150° C. for 20 min under microwave radiation. The reaction mixture is filtered through a small plug of Celite and concentrated. Final purification using preparative RP LC-MS affords N2-{2-Isopropoxy-4-methyl-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-phenyl}-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (37). MS (ES+): 634.3 (MH+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=2)[NH:5][C:4]1=[O:20])[CH3:2].[CH2:23]([C@@H:26]([N:34]=[C:35]=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:21]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:19])[CH2:15][CH2:16][C:17]#[N:18])=[CH:10][CH:9]=2)[N:5]([C:35]([NH:34][C@H:26]([CH2:23][CH:24]=[CH2:25])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:36])[C:4]1=[O:20])[CH3:22]
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)CCC#N)cc1
Reactant: C=CC[C@@H](N=C=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(=O)CCC#N)cc1)c1ccc(C)cc1

Procedure:
According to the procedure of Example 21, Step B, 1.29 gm (4.3 mmol) of 3,3-diethyl-4-(RS)-[4-(1-oxo-3-cyanopropyl)phenoxy]azetidin-2-one, 0.965 gm (5.15 mmol) of (R)-α-allyl-4-methylbenzyl isocyanate, 59 mg (0.43 mmol) of potassium carbonate in 20 mL of DMF gave, after EPLC purification on 1 kg of silica eluting with 8 L of 72:28 hexanes: ethyl acetate 1.0 gm of the product as an oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:28])=[C:5]([CH:10](O)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([F:28])=[C:5]([CH:10]2[O:26][CH2:25][C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@H](CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc(F)c(C#N)c3F)OC[C@@H]2C1
Temperature: 100 °C

Procedure:
tert-Butyl (3S)-4-[2-(3-cyano-2,4-difluorophenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (1.2 g, 3.0 mmol) and cyanomethylenetri-n-butylphosphorane (1.31 g, 5.44 mmol) were dissolved in 5 mL of benzene. The reaction mixture was degassed and heated to 100° C. for 16 h. LC-MS analysis showed product peak at 2.07 min (M+1=380). The reaction was cooled and evaporated to dryness. The residue was purified by MPLC chromatography through an 80 g Redi-sep column eluting with a 40% EtOAc/60% hexane mixture to yield a cis-trans mixture of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:40][CH:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)=[O:28])=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Reactant: CN1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a mixture of 0.11 g (0.27 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-20), 0.19 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.30 mmole) of 4-amino-1-methyl-piperidine in 3.0 mL of dimethylformamide was added 0.13 g (0.30 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-75:25) gave 0.10 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-21) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[O:11])=[CH:5][N:4]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]=[O:11])[Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][N:4]=1
Reactant: COc1ccc(NC=O)cn1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(N(C=O)[Si](C)(C)C)cn1
Temperature: 10 °C
Yield: 87 %

Procedure:
N-(2-Methoxy-5-pyridyl)formamide (30.4 g, 0.2 mol) was added to 200 ml benzene. This was stirred with a mechanical stirrer under argon at 10° C. Trimethylsilyl chloride (25 g, 0.23 mol) was added. While stirring at 10° C., triethylamine (21 g, 0.21 mol) dissolved in 50 ml benzene was added dropwise over 0.5 hour. The slurry was warmed to room temperature and after 0.5 hour filtered. The salt cake was washed with 100 ml benzene and the combined filtrates concentrated on a rotary evaporator at 30° C. under aspirator vacuum. The dark liquid product was distilled under reduced pressure. A clear liquid, 39 g, 87% yield, (b.p. 87° C./0.25 mmHg). The product was stored under argon.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:17][CH:13]1[CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCC1
Reactant: Clc1nc2ccncc2nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc2cnccc2nc1NC1CCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A mixture of 2,3-dichloropyrido[3,4-b]pyrazine (100 mg, 0.500 mmol), cyclobutanamine (47.0 μL, 0.550 mmol) and DIPEA (260 μL, 1.500 mmol) was stirred at 0° C. for 15 min then at rt for 30 min. Saturated aqueous NH4Cl was added to the mixture and the product was extracted with EtOAc. The combined organic layers were filtered through a pad of silica (EtOAc wash) and the filtrate was concentrated to afford 3-chloro-N-cyclobutylpyrido[3,4-b]pyrazin-2-amine (116.1 mg, 99%) as a yellow solid, which was used without further purification. ESI-MS m/z [M+H]+ 235.2.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][CH2:11][CH2:12]O.Br>ClCCl>[BrH:10].[Br:10][CH2:11][CH2:12][NH:9][CH:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(N)c1ccccc1
Reactant: OCCBr
Agent: Br
Solvent: ClCCl
Product: CC(NCCBr)c1ccccc1
Temperature: 51 °C
Reaction time: 50 h
Yield: 109.8 %

Procedure:
76.61 g (630 mmole) of α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g (760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml (2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate and then dried to obtain 128.9 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CCBr)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>>[N:19]1([CH2:2][CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: c1nc[nH]n1
Product: Oc1ccc(OCCn2cncn2)cc1

Procedure:
In a manner analogous to that described in Example 1(b), from 1-benzyloxy-4-(2-bromoethoxy)benzene and 1H-1,2,4-triazole, 4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenol was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([NH:1][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1cc(N)cc(Br)c1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC2CCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl 3-amino-5-bromobenzoate (2 g, 8.73 mmol) and cyclopentanone (2.2 g, 26.1 mmol) in methanol (20 mL), acetic acid (1.04 g, 17.4 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (1.37 g, 21.83 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford desired compound (1.6 g, 61%).
Reaction SMILES: [CH2:1]=[CH:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[F:16][CH:17]([C:21]([F:24])([F:23])[F:22])[C:18](Cl)=[O:19].O>ClCCl>[F:16][CH:17]([C:21]([F:24])([F:23])[F:22])[C:18]([O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:2]=[CH2:1])=[O:19]
Reactant: O=C(Cl)C(F)C(F)(F)F
Reactant: C=C[C@H](O)CCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(CCCCC)OC(=O)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In 200 ml of dichloromethane were dissolved 28 g (0.22 mol) of (R)-(-)-1-octen-3-ol (92%ee) and 21 ml (0.26 mol) of pyridine, and then 39.5 g (0.24 mol) of 2,3,3,3-tetrafluoropropionyl chloride was dropwise added to the above-obtained solution while the solution was being cooled with ice. The resulting mixture was stirred at room temperature for 1 hour, subsequently water was added thereto, and then the reaction mixture was subjected to extraction with ether. The resulting extract was washed with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate, and brine, and then dried with magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and the residual product was distilled at 95° C. under 25 mmHg, thereby obtaining 42.3 g of 1-octen-3-yl 2,3,3,3-tetrafluoropropionate in a yield of 76%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][N:23](C(OC(C)(C)C)=O)[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:32])[CH2:22][NH:23][CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
N-tert-Butoxycarbonyl-N-methyl-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (65) (2.19 g; 4.99 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 2.5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.65 g) as a white solid. CIMS: MH+ 339
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)O)[C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[OH-].[K+]>C(Cl)Cl.CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:18]=[CH:17][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)=[CH:25][CH:24]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(F)cc2)CCN(C)CC1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2C=Cc2ccc(F)cc2)CCN(C)CC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 7.1 %

Procedure:
To a solution of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-fluorophenyl)ethanol (150 mg, 0.42 mmol) in DCM (7 mL), triethylamine (0.088 mL, 0.63 mmol) was added and stirred for 10 min, methane sulfonyl chloride (0.036 mL, 0.47 mmol) were added slowly at 0° C. and stirred at RT for 2 h. Reaction was monitored by TLC. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was dissolved in NMP (0.8 mL), KOH powder (166 mg, 2.97 mmol) was added at RT and heated at 90° C. for 14 h. Reaction was monitored by LCMS. The reaction mixture was diluted with methanol, inorganic material was filtered off and the compound was purified by reverse phase chromatography to afford 10 mg of product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.70-7.50 (m, 4H), 7.30 (s, 1H), 7.20-7.00 (m, 3H), 6.80-6.70 (d, 1H), 3.90-3.75 (m, 4H), 3.50-3.40 (m, 4H), 3.15 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]([Sn](C)(C)C)[N:17]=[N:16][N:15]=3)[CH:11]=[CH:10][C:9]=2[NH2:23])=[CH:4][CH2:3]1.[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:11]=[CH:10][C:9]=2[NH:23][C:41]([C:30]2[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=2)=[O:42])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(-c3nnnn3[Sn](C)(C)C)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(-c3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-(4,4-dimethyl-cyclohex-1-enyl)4-(1-trimethylstannanyl-1H-tetrazol-5-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.347 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 148 mg, 0.480 mmol), PyBroP (259 mg, 0.555 mmol) and DIEA (151 μL, 0.867 mmol) according to the procedure in Example 11, step (f) (103 mg, 57%). Mass spectrum (ESI, m/z): Calcd. for C26H34N8O2Si, 519.2, found 519.1
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15]>CCO>[CH3:14][C:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:13][CH2:12]1
Reactant: N
Reactant: CC1(c2cc3cc(Cl)ncc3[nH]2)CC1
Solvent: CCO
Product: CC1(c2cc3cc(N)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
In a 100 mL autoclave, a solution of 5-chloro-2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridine (1.0 g, 4.9 mmol) and CuSO4.5H2O (100 mg, 0.4 mmol) in aqueous ammonia (60 mL) and EtOH (20 mL) was heated to 200° C. and stirred at this temperature for 8 hours. The mixture was allowed to cool down to room temperature. The alcohol was removed under vacuum. The resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and purified by chromatography on silica gel (2% CH3OH in dichloromethane as eluant) to afford 2-(1-methylcyclopropyl)-1H-pyrrolo[2,3-c]pyridin-5-amine (250 mg, 27%). 1H-NMR (DMSO, 300 MHz) δ 7.96 (s, 1H), 6.37 (s, 1H), 5.88 (d, J=1.2, 1H), 5.01 (br s, 2H), 1.41 (s, 3H), 0.98 (t, J=2.1, 2H), 0.80 (t, J=2.1, 2H).