Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]([CH3:27])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>C(#N)C>[CH3:27][C:15]([NH:14][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CC(C)(N)COc1ccc(C#N)cn1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)COc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g, 0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen, was added 6-(2-amino-2-methyl-propoxy)-nicotinonitrile (0.1 g, 0.508 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2% MeOH/CH2Cl2 to provide the desired compound as a white solid. MS (DCI) m/z 352 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H, s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.08 (3H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:14]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].O.NN>CO.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:14]2[N:13]([CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:18][CH2:17][S:16][C:15]=2[CH:19]=1
Reactant: CN(CCCN1CCSc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(CCCN1CCSc2cc(N)ccc21)C(=O)OC(C)(C)C
Yield: 99.8 %

Procedure:
A suspension of tert-butyl methyl(3-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)propyl)carbamate (0.6 g, 1.633 mmol) in dry methanol (10 mL) was treated with Raney-Nickel (0.1 g, 1.633 mmol) followed by hydrazine hydrate (0.595 mL, 16.33 mmol) at room temperature. The resulting mixture was refluxed for 10 minutes in a pre-heated oil bath. The reaction was then brought to room temperature, filtered through a pad of Celite, and washed with methanol (3×10 mL). The combined methanol layers were evaporated, and the crude material was purified by flash column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain title product (0.55 g, quantitative) as a brown syrup. 1H NMR (DMSO-d6) δ 6.46 (d, 1H, J=9.6 Hz), 6.25-6.21 (m, 2H), 4.44 (s, 2H), 3.32-3.28 (m, 2H), 3.19 (t, 2H, J=6.9 Hz), 3.04 (t, 2H, J=7.2 Hz), 3.00-2.97 (m, 2H), 2.77 (s, 3H), 1.74-1.62 (m, 2H), 1.38 (s, 9H); ESI-MS (m/z, %): 338 (MH+, 100), 337 (96), 282 (54).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1Cl.NC1N2C=CN=C2C(C(NCC2CCN(CCCC)CC2)=O)=CC=1Cl>>[NH2:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:16][CH2:15]2)=[O:12])=[CH:4][CH:3]=1
Reactant: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Agent: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Product: COCCCN1CCC(NC(=O)c2ccc(N)n3ccnc23)CC1

Procedure:
The title compound was prepared according to the procedure of EXAMPLE 2 using 5-amino-6-chloro-N-[1-(3-methoxypropyl)-4-piperidinyl]imidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 3), instead of 5-amino-N-[(1-butyl-4-piperidinyl)methyl]-6-chloroimidazo[1,2-a]pyridine-8-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].B1C2CCCC1CCC2.[OH-].[Na+].OO.[O-:34]S([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:34])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=S([O-])[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 1-chloro-2-(trifluoromethyl)-4-(4-vinylphenoxy)benzene (3 g, 10.04 mmol) in THF (50 mL) was added 9-BBN (24.11 mL, 12.05 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 0.5 h, then the temperature was allowed to warm up to room temperature. NaOH (13.39 mL, 40.2 mmol) and H2O2 (14.36 mL, 141 mmol) was added. The mixture was then heated at 60° C. for 2 h. Na2SO3 was added to quench the reaction after cooling. Purification via flash chromatography then afforded the title compound (2.2 g, 6.95 mmol, 69.2% yield). LCMS: rt=3.55 min, [M+H+-H2O]=299
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([C:14]#[C:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:14]=[C:15]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[N:8]([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: CCOC(C#Cc1cnc(Cl)nc1NC1CCCC1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc2cnc(Cl)nc2n1C1CCCC1
Temperature: 65 °C
Yield: 82.2 %

Procedure:
A mixture of [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl amine (5.21 g, 16 mmol) in THF is added 1M tetra-n-butylammonium floride in THF (TBAF) (97 mL, 97 mmol) and heated to 65° C. for 2 hour. Solvent is removed and column is run using heptane/ethyl acetate from 5% to 15% to give 2-chloro-7-cyclopentyl-6-diethoxymethyl-7H-pyrrolo[2,3-d]pyrimidine (4.26 g, 82%). MS (ESI) m/z 324.5 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:9][C:10](=[O:21])[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8].[CH3:22][C:23]1[CH2:28][CH2:27][CH2:26][C:25]([CH3:30])([CH3:29])[C:24]=1[CH:31]=[CH:32][C:33](Cl)=[O:34]>C1COCC1.CCOCC>[CH2:3]([O:9][C:10](=[O:21])[CH:11]([C:33](=[O:34])[CH:32]=[CH:31][C:24]1[C:25]([CH3:29])([CH3:30])[CH2:26][CH2:27][CH2:28][C:23]=1[CH3:22])[C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: CC1=C(C=CC(=O)Cl)C(C)(C)CCC1
Reactant: CCC=CCCOC(=O)CC(=O)OCCC=CCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC=CCCOC(=O)C(C(=O)C=CC1=C(C)CCCC1(C)C)C(=O)OCCC=CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a suspension of 2.10 g 60% sodium hydride in 20 ml of THF, a solution of 14.00 g malonic acid dihex-3-enyl ester in 20 ml of THF were dropped in at 0-5° C. The reaction mixture was stirred 1 hour at room temperature. Then a solution of 11.9 g 3-(2,6,6-trimethyl-cyclohex-1-enyl)-acryloyl chloride (Shimasaki et al., Chem. Pharm. Bull., 43 (1995) 1, 100-107) in 40 ml of THF was dropped in and the reaction mixture was stirred at room temperature for 21 hours. Then the reaction mixture was diluted with ether and the organic phase was washed with water, dried, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 4.22 g of a yellow oil.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[C:9]([C:13]1[CH:47]=[CH:46][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45])[CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:31]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>O1CCOCC1>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2/[CH:25]=[CH:26]/[CH:27]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]3[O:35][C:2](=[O:3])[NH:37][N:36]=3)=[CH:32][CH:31]=2)[CH2:40][CH2:41][CH2:42][CH2:43][C:44]#[N:45])=[CH:46][CH:47]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC#N)CCc2ccc(C(=O)NN)cc2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCCCC#N)CCc2ccc(-c3n[nH]c(=O)o3)cc2)cc1
Yield: 23 %

Procedure:
A solution of 566.6 mg (2.86 mmol) of trichloromethyl chloroformate in 2.5 ml of dry dioxane is mixed with 1.0 g of 4-[3-((E)-2-{2-[(4-tert-butylbenzyl)oxy]phenyl}vinyl)-7-cyanoheptyl]-benzohydrazide from Example 97A (crude product) in 7.5 ml of dioxane and heated to reflux for 3 hours. The mixture is then directly taken up on silica gel, concentrated to dryness and purified by flash chromatography (mobile phase: dichloromethane/methanol 5:1). 236 mg (0.429 mmol, 23% yield based on two stages) of a solid are obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:19][CH3:20])[C:14]4[CH2:21][CH:22]5[NH:26][CH:25]([C:13]=4[C:12]=3[C:11]=2C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34]>C(OCC)C>[ClH:34].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[C:14]2[CH2:21][CH:22]4[NH:26][CH:25]([C:13]3=2)[CH2:24][CH2:23]4)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C1CCC(C2)N1

Procedure:
The product of step B was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 27, step D. The crude material was purified by flash column chromatography (SiO2, 99:0.9:0.1 to 80:18:2 dichloromethane/methanol/ammonium hydroxide) and semi-preparative HPLC. The free base was dissolved in methanol and treated with an excess of HCl in diethyl ether. The solution was concentrated in vacuo and the residue lyophilized from water/acetonitrile to give 2-phenylsulfonyl-5-ethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (28 mg, 100%, AUC HPLC >99%) as a white solid: mp 200-204° C. dec; 1H NMR (CD3OD, 300 MHz) δ 8.28 (d, J=1.8 Hz, 1H), 7.91-7.98 (m, 2H), 7.72 (dd, J=8.7; 1.8 Hz, 1H), 7.49-7.63 (m, 4H), 5.25-5.32 (m, 1H), 4.49-4.58 (m, 1H), 4.10-4.28 (m, 2H), 3.42-3.56 (m, 1H), 3.00-3.11 (m, 1H), 2.23-2.52 (m, 3H), 1.88-2.05 (m, 1H), 1.32 (t, J=7.2 Hz, 3H); ESI MS m/z 367 [M+H]+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([N:9]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH3:10])([CH3:8])[CH3:7].CN([CH:21]=[O:22])C>>[CH:6]([N:9]([C:11]1[CH:12]=[C:13]([OH:17])[C:14](=[CH:15][CH:16]=1)[CH:21]=[O:22])[CH3:10])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)N(C)c1cccc(O)c1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(C)c1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
11 g (0.118 mol) of phosphorus oxychloride are cautiously added to 33 ml of dry DMF at −5° C. within a period of 5 minutes, during the course of which the temperature of the reaction solution should not exceed 10° C. Subsequently, a solution of 19.4 g (0.1176 mol) of 3-(N-isopropyl-N-methylamino)phenol in 25 ml of dry DMF is added thereto within a period of 10 minutes, during the course of which the temperature of the reaction solution should not exceed 20° C. When the addition is complete, the reaction solution is heated for 2 hours at 90° C. and then immediately poured onto 150 g of ice. The crude mixture is extracted three times with 100 ml of chloroform. The combined organic phases are concentrated under a high vacuum. The oily residue is purified by column chromatography on silica gel (eluant n-hexane/chloroform 95:5). Yield: 5.8 g (26%), colourless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH:22]=[CH:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CC=Cc2cccs2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCCc2cccs2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In methanol (70 ml) was dissolved 1,4-bis(tert-butoxycarbonyl)-2-[3-(thien-2-yl)-2-propenyl]piperazine (1.01 g). In the resulting solution was suspended 10% palladium-carbon (50% wet, 431 mg), followed by vigorous shaking at room temperature for 6 hours under a hydrogen gas atmosphere of 1 atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1 to 2:1), whereby the title compound (975 mg) was obtained as colorless powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](OCC)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([N:23](CC)CC)C.C(CC(N)=S)#N>CCO>[C:21]([CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[N:12]=1)#[N:23]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Agent: N#CCC(N)=S
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Temperature: 25 °C

Procedure:
N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide (Intermediate 1)(1.0 g; 2.79 mmol; 1 eq.) is dissolved in EtOH (25 ml). Triethylamine (980 μl; 6.98 mmol; 2.50 eq.) and 2-cyanothioacetamide (Aldrich)(279.7 mg; 2.79 mmol; 1 eq.) are added. The mixture is stirred 2 h30 at rt. Solvents are evaporated and the crude product is purified by flash chromatography, with cyclohexane/EtOAc gradient as eluent. Compound (3) is isolated as a white-off powder (680.3 mg; 88%). HPLC (method A), Rt 2.30 min (purity: 92.79%). Compound (3) is further crystallized in EtOAc, affording a new batch as colorless needles (412.60 mg; 52.75%). 1H NMR (DMSO-d6, 300 MHz) δ 2.13 (s, 3H), 2.47 (s, 3H), 4.61 (s, 2H), 7.71 (s, 1H), 12.12 (br s, 1H). M− (ESI): 277; M+ (ESI): 279. HPLC (method A), Rt: 2.28 min (purity: 99.5%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Br)ccc1CO
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 4-bromo-2-methylbenzaldehyde (1.99 g, 10 mmol) in ethanol (100 mL) was added sodium borohydride (0.76 g, 20 mmol) in portions at 0° C. The mixture was stirred for 30 minutes and warmed to 20° C. and stirred at the same temperature for 12 hours. The mixture was concentrated in vacuo to give (4-bromo-2-methylphenyl)methanol (1.3 g, 65%).
Reaction SMILES: [CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>>[CH2:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]([OH:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:14]([CH3:26])[CH:13]=1)([C:6]1[S:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1cc(C)cs1

Procedure:
Using a procedure analogous to Example 134B, 1-{4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-4,4-dimethyl-pentan-3-one and NaBH4 give the title compound (quant).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[F:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:25]1[CH2:26][CH2:27][CH:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([F:17])=[CH:29][CH:28]=2)[CH2:24]1)=[O:15]
Reactant: Fc1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(Cc2ccc(F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-fluorobenzyl)pyrrolidine hydrochloride (12.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.1 mg). Calcd for C21H18ClFN2O2: 384.1041, found 384.1042.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:2][C:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1)=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1cc([N+](=O)[O-])cc2c1OCC2
Product: CN(C)C=CC(=O)c1cc([N+](=O)[O-])cc2c1OCC2
Yield: 80 %

Procedure:
7-Acetyl-5-nitro-2,3-dihydrobenzofuran (D9) (500 mg) was stirred and heated to 80° C. for 1 h with tert-butoxy-bis (dimethylamino) methane (1.08 ml), then the mixture was cooled and partitioned between Na2 CO3 and ethyl acetate. The organic phase was dried (Na2 SO4) and the solvent evaporated under reduced pressure to leave the title compound (0.5 g, 80%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.ClC(N(C)C)=C(C)C.Cl.[NH2:18][CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[C:27]#[N:28])=[O:21].C(N(C(C)C)C(C)C)C>O1CCOCC1>[C:27]([C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20](=[O:21])[CH2:19][NH:18][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])#[N:28]
Reactant: N#C[C@@H]1CCCN1C(=O)CN
Reactant: O=C(O)c1c[nH]nn1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1H-1,2,3-triazole-4-carboxylic acid (0.092 g, 0.814 mmol) was dispersed in dry dioxane (3 mL) in a round bottom flask with nitrogen. To this 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.151 ml, 1.139 mmol) was added and the reaction was stirred for 30 minutes at room temperature. The starting material dissolves over time. Then (S)-1-(2-aminoacetyl)pyrrolidine-2-carbonitrile hydrochloride (0.247 g, 1.302 mmol) with N-ethyl-N-isopropylpropan-2-amine (0.307 ml, 1.709 mmol) was added and the mixture was stirred for 2 h, evaporated to dryness and redissolved in ethyl acetate. Followed by washing with 0.1N citric acid and saturated sodium bicarbonate and brine. After drying over sodium sulfate, filtration and evaporation, the product was purified using column chromatography.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35]>CCCCO.CS(C)=O>[F:35][C:34]([F:37])([F:36])[CH:33]([OH:38])[CH:32]([NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1)[CH2:39][CH3:40]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: CCC(N)C(O)C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (300 mg, 1.05 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (1.4 ml, 10 eq, 8 mmol) followed by 3-amino-1,1,1-trifluoropentan-2-ol (1 g, 6.4 mmol). The flask was fitted with a condenser and the reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 ml) and water (50 ml), the aqueous phase was extracted with more EtOAc (2×25 ml), and the combined organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluted with CHCl3:MeOH (100:0→95:5), to afford the title compound as a colorless film (42 mg, 9.4%). δH (CDCl3, 500 MHz) 1.04 (3 H, t, J 7.5, CHCH2CH3) 1.56 (6 H, d, J 7.5, CH[CH3]2), 1.8-1.73 (2 H, m, CHCH2CH3), 4.13-4.07 (1 H, m, CHMe2), 4.22-4.2 (1 H, m, CHEt) 4.57-4.55 (1 H, m, CHOHCF3), 4.71 (2 H, s, b, NHCH2Ar), 5.08 (1 H, s, b, NH), 7.2 (1 H, dd, J 5, 10 ArH), 7.51 (1 H, s, ArH), 7.64 (1 H, d, J 10, ArH), 8.46 (1 H, d, J 5, ArH), 8.55 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.28 (C), 154.72 (C), 149.07 (CH), 148.47 (CH), 135.44 (CH), 134.83 (C), 134.48 (CH), 124.12 (C), 123.44 (CH), 114.62 (C), 73.1 (CH), 55.88 (CH), 46.70 (CH), 41.78 (CH2), 23.68 (CH2) 22.36 (2×CH3), 11.55 (CH3); 19FNMR δ −74.83; m/z 424.2 (M+H)
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].OO.[OH:33]S(O)(=O)=O>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]([NH2:24])=[O:33])[C:17](=[O:28])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C2CC(=O)N(c3cccc(C#N)c3)C2)cc1OC1CCCC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(N)=O)c3)C2)cc1OC1CCCC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (12.5 mg, 0.033 mmol) in ethanol (0.5 mL) was added 2 μL of a 25% NaOH solution, followed by 29 μL of 35% H2O2. The temperature of the reaction mixture was kept at 50° C. for 3 h. Upon completion, 5% H2SO4 was added until the mixture was neutral (pH 7). The reaction mixture was extracted with EtOAc and dried with MgSO4. Purification on silica gel afforded the product as a white solid. Yield: 94%.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:32])=[CH:17][N:16]=1.C(=O)([O-])[O-]>CCOCC>[Cl:32][C:18]1[C:19]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:13][C:10]2[CH:11]=[CH:12][C:3]3[N:2]([CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[CH:9]=2)=[N:16][CH:17]=1
Reactant: CN1CCCCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCCN3C)ncc1Cl
Reaction time: 0.5 h

Procedure:
Following the procedure of Example 101b, 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (33 mgs, 0.19 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (1.2 eq) were reacted except that following completion of the reaction a precipitate ensued. This mixture was diluted with ether and filtered. The resulting solid was treated with MP-carbonate (3 eq), stirred for 30 min, filtered and concentrated to give 2-[5-Chloro-2-(1-methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a off-white/yellow solid (39.01 mgs). MP=170-172° C. 1H-NMR (CDCl3) δ 11.06 (s, 1H), 8.70 (d, J=8.3 Hz, 1H), 8.08 (s, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.30-7.27 (m, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.81 (s, 2H), 6.20 (br s, 1H), 3.05 (d, J=4.8 Hz, 3H), 2.83 (s, 5H), 2.77-2.73 (m, 2H), 1.84-1.75 (m, 2H), 1.64-1.55 (m, 2H); LC/MS (ESI+): 437.30 (M+H).