Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:23])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=1[F:22])=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCOCC>[BH4-].[Zn+2].[BH4-].O>[Si:1]([O:8][C@@H:9]([CH3:23])[C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:13]=1[F:22])[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)c1cccc(C(F)(F)F)c1F
Agent: [BH4-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](O)c1cccc(C(F)(F)F)c1F
Reaction time: 2 h

Procedure:
To a solution of 112 (1.374 g, 3.921 mmol) and Et2O (20 mL) cooled to 0° C. was added a solution of zinc borohydride (8.46 mL, 1.176 mmol) was added and the reaction was stirred for 2 h. Water was added slowly and the mixture was extracted with ether. The organic layer was washed with water and brine then dried, filtered, and concentrated to afford (1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(2-fluoro-3-(trifluoromethyl)phenyl)propan-1-ol (114) which was used without additional purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3COCCO3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.58 g (1.84 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole (example 71, part B) and 0.51 g (2.39 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography over silica gel, 0.18 g (20% of yield) of the expected acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:42])=[C:26]([CH:41]=1)[O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:38]([NH:37][C:35]1[S:34][C:32]2[C:31]([N:36]=1)=[CH:30][CH:29]=[C:28]([O:27][C:26]1[CH:41]=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]4([C:14]#[N:15])[CH2:13][CH2:12]4)[C:2]=3[Cl:1])[CH:23]=[CH:24][C:25]=1[F:42])[N:33]=2)(=[O:40])[CH3:39]
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(N)ccc3F)nc2s1
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C62(ii) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(5-amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) produced in Example C73(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (50 mg, 29%) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][CH2:22][OH:23])[CH2:19][C:18](=O)[NH:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:21][CH2:22][OH:23])[CH2:19][CH2:18][N:17]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:16]2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CCO)CNC(=O)C2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([O:4]/[CH:5]=[CH:6]/[CH3:7])(=[O:3])[CH3:2].[CH3:8][N:9]([CH:11](N(C)C)OC(C)(C)C)[CH3:10]>>[CH3:8][N:9]([CH3:11])/[CH:10]=[CH:2]/[C:1]([O:4]/[CH:5]=[CH:6]/[CH3:7])=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: C/C=C/OC(C)=O
Product: C/C=C/OC(=O)/C=C/N(C)C
Yield: 90.9 %

Procedure:
A solution of 20.0 g (0.2 mole) of trans-propenyl acetate and 101.0 g (0.6 mole) of bis(dimethylamino)-tert.-butoxymethane under argon was heated at 50° C. overnight (161/2 hours). The excess reagent was removed by vacuum distillation (0.7 mmHg, oil bath at 50° C.). The residue was chromatographed rapidly on 300 g of silica gel 60 eluting with ethyl acetate/hexane (2:3 parts by volume) to give 28.2 g (91%) of trans-3-(dimethylamino)-2-propenoic acid, trans-propenyl ester which was used in the next step with no further purification. This material was sublimed (to remove yellow color) at 40°-50° C. 0.2 mmHg. The analytical sample was recrystallized from pentane. Mp 48°-48.5° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C:12]1=[O:21])[CH3:7].O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:17][C:18]([CH:29]=[O:30])=[C:19]([CH3:20])[C:13]=2[C:12]1=[O:21])[CH3:23]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1CCc2[nH]cc(C)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A stirred solution of N,N-dimethylformamide (2 ml) was added slowly with 104 μl of phosphorus oxychloride under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (249 mg, 1 mmol) in 2 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (15 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (105 mg, 38%) as a pink oil which was used as such.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[NH:23][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc[nH]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccc[nH]4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 143 mg (1.5 mmol) of pyrrole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in DIPE yield 4-(3-chloro-phenylamino)-3-[(1H-pyrrol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=8.2; FAB-MS: (M+H)+=340.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.ClCCl>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2sc3c(c2c(-c2cncnc2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2sc3c(c2c(-c2cncnc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3

Procedure:
A sample of the product from Example 1 may be dissolved in a mixture of methanol and dichloromethane (1:1) loaded onto a Chiralpak IC column (250×20 mm internal diameter) and eluted with methanol/CO2 (60:40) at ambient temperature and a flow rate of 60 g/min. Fractions containing a single enantiomer may be combined and evaporated under reduced pressure to give the product enantiomer. Chiral purity may be assessed by chiral hplc using a Chiralpak IC column eluting with hexane/isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[CH:20]=[C:19]([CH3:30])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH2:28]3)[CH:20]=[C:19]([CH3:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(N2CCC(O)CC2)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(N3CCC(O)CC3)n2)ccc1-n1cnc(C)c1
Yield: 82 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (41 mg, 0.20 mmol) and 1-(2-chloro-6-methyl-pyrimidin-4-yl)-piperidin-4-ol (50 mg, 0.22 mmol) in analogous manner as described in example 90. It was obtained in 82% yield as a light brown solid. MS ISP (m/e): 395.2 (100) [(M+H)+]; 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.23 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.18 (m, 2H), 7.01 (s, 1H), 6.22 (s, 1H), 4.75 (d, 1H), 4.03 (br m, 2H), 3.78 (s, 3H), 3.75 (m, 1H), 3.23 (m, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 1.76 (m, 2H), 1.32 (m, 2H).
Reaction SMILES: [C:1]1([O:7][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC1CCC=CC=1)C>CCOCC>[CH2:8]([O:7][C:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1)[CH3:9]
Reactant: CCOc1ccccc1
Agent: CCOC1=CC=CCC1
Solvent: CCOCC
Product: CCOC1=CCC=CC1

Procedure:
A solution of 59.5 g. of phenetole (ethyl phenyl ether) in 200 ml. of dry ether and 800 ml. of liquid ammonia which was distilled from sodium was placed in a 2 1. three necked flask fitted with a mechanical agitator, dry ice condenser and dropping funnel and cooled with a dry ice - ethyl alcohol bath. To this mixture was added 14.1 g. of lithium wire in small pieces. After the addition was complete, absolute ethyl alcohol (about 400 ml.) was added until the blue color disappeared. The resulting mixture was left in a good exhaust hood for the ammonia to evaporate. Water (200 ml.) was cautiously added to the resulting mixture and the precipitate filtered off. The organic layer was separated and the water layer extracted three times with 50 ml. of ether. The combined organic solutions were washed neutral with water and dried over anhydrous potassium carbonate. The solvent was removed by atmospheric distillation through a 37 cm. column packed with glass helices. There was produced 45 g. (75% of theory). This material analyzed as 86% 1-ethoxy-1,3-cyclohexadiene.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14]2[O:18][NH:17][C:16](=[O:19])[CH:15]=2)[CH2:11][CH2:10][N:9]1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Br>[CH2:1]([C@H:8]1[CH2:13][C@@H:12]([C:14]2[O:18][NH:17][C:16](=[O:19])[CH:15]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccccc3)C2)o[nH]1
Reaction time: 16 h

Procedure:
To (2R,4S)-methyl 2-benzyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.47 g) was added HBr (33% in HOAc, 10 mL) and the solution was stirred for 16 h. The volatiles were concentrated and the residue purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-40% acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 15 minutes with a flow of 100 mL/minutes. The title compound was isolated (0.26 g, 29%): 1H NMR (600 MHz, dmso) δ 1.07 (m, 1H), 1.26-1.45 (m, 1H), 1.75 (m, 2H), 2.53 (m, 2H), 2.58-2.67 (m, 2H), 2.69 (m, 1H), 2.97 (m, 1H), 5.66 (s, 1H), 7.08-7.34 (m, 5H); [α]20D +67.8 (MeOH/H2O 1:1, c=1); HRMS Calculated for [C15H19N2O2]+: 259.1447. found: 259.1442.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[N:15]([C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]2[CH2:26][CH2:27][CH2:28][C:20]=2[N:19]=1)=[C:16]=[S:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:25][O:24][C:22]1[C:21]2[CH2:26][CH2:27][CH2:28][C:20]=2[N:19]=[C:18]([NH:15][C:16]([NH:1][S:2]([C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[S:17])[N:23]=1
Reactant: COc1nc(N=C=S)nc2c1CCC2
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=S)Nc1nc2c(c(OC)n1)CCC2
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A mixture of 4.3 g of methyl 2-(aminosulfonyl)-benzoate, 4.2 g of 6,7-dihydro-2-isothiocyanato-4-methoxy-5H-cyclopentapyrimidine and 2.2 g of anhydrous potassium carbonate in 70 ml of acetone was warmed to 40° with stirring. After 2 hours, a thick precipitate formed and stirring was continued for three more hours at ambient temperature. The precipitate was filtered, suspended in 150 ml of water, stirred and the pH adjusted to 2 by the addition of hydrochloric acid. The white solid was filtered, washed with cold water and dried to yield 4.2 g of product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][O:38][C:34]=2[CH:33]=1>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.COCCOC>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[O:24])=[CH:9][C:10]=1[C:32]1[CH:46]=[CH:45][C:35]2[C:36]([CH:39]3[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]3)=[N:37][O:38][C:34]=2[CH:33]=1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc2c(C3CCNCC3)noc2c1
Yield: 70.7 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 18, 50 mg), DME (3 ml), aqueous sodium carbonate (1M, 2 ml), tetrakis(triphenylphosphine)palladium (20 mg) and 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole (44 mg, 147 μmol) were heated together at 80° C. under nitrogen for 18 h. The solvent was evaporated, and the residue was purified by column chromatography on silica (10 g) eluting with dichloromethane:ethanol:ammonia (100:8:1) to give the title compound (43 mg).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[N:20][NH:21][CH:22]=2)=[C:9]([O:23]C)[C:8]1=[S:25].B(Br)(Br)Br>C(Cl)Cl>[C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[N:19]=[N:20][NH:21][CH:22]=2)=[C:9]([OH:23])[C:8]1=[S:25]
Reactant: COc1c(CCCCCc2c[nH]nn2)ccn(-c2ccccc2C)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1-n1ccc(CCCCCc2c[nH]nn2)c(O)c1=S
Yield: 66.5 %

Procedure:
Reaction of 165c (0.072 g, 0.195 mmol) and 1M BBr3 (0.30 mL) in CH2Cl2 (8 mL) within 48 h as described for the synthesis of 148a gave compound 167c (0.046 g, 67%) as olive green solid. 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.61 (m, 1H), 7.47 (s, 1H), 7.21 (m, 1H), 6.97 (m, 1H), 6.76 (m, 1H), 4.52 (m, 1H), 4.45 (t, J=6.8 Hz, 1H), 2.38 (s, 1H), 2.01 (m, 2H), 1.43 (m, 1H). 13C NMR (100 MHz, CD3OD) δ 146.74, 135.53, 130.65, 129.46, 128.69, 128.21, 125.88, 122.79, 53.41, 49.83, 29.42, 27.32, 22.98, 20.55. HRMS (EI) calcd for C19H22N4OS [M]+ 354.151. found 354.1509.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]([NH:12][C:13]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[O:29])[CH2:23]4)[N:14]=3)=O)[CH2:9][CH2:8]2)[CH:6]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Zn].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2([C:10]3[NH:12][C:13]4=[N:14][C:15]([N:22]5[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([N:30]6[CH2:34][CH2:33][CH2:32][CH2:31]6)=[O:29])[CH2:23]5)=[CH:16][CH:17]=[C:18]4[N:19]=3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C([C@@H]1CCCN(c2ccc([N+](=O)[O-])c(NC(=O)C3(n4cc(Cl)cn4)CC3)n2)C1)N1CCCC1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 103.7 %

Procedure:
Into a flask was added (R)-1-(4-chloro-1H-pyrazol-1-yl)-N-(3-nitro-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-2-yl)cyclopropanecarboxamide (107 g, 219.29 mmol) and acetic acid (750 mL, 6.74 mol). The mixture was stirred for 5 min. Zinc powder (71.70 g, 1.10 mol) was added. An exotherm to 79° C. was observed over a period of 30 sec. The reaction mixture was warmed to 100° C. and stirred for 2 h. The mixture was cooled to 50° C. and water (750 mL) was added. The mixture was stirred for 10 min and cooled to 10° C. Ethyl acetate (500 mL) was added and the mixture was stirred for 20 min and filtered through Celite rinsing with ethyl acetate (300 mL). The filtrate was cooled to 10° C. and aqueous ammonium hydroxide (936.92 mL, 6.74 mol) was added dropwise over a period of 20 min. The layers were separated and the organics were washed with a mixture of water:brine (1:1, 500 mL), and concentrated under reduced pressure. Ethyl acetate (200 mL) was added and the mixture was concentrated under reduced pressure followed by the addition of acetonitrile (500 mL). The mixture was concentrated to dryness at 45° C. to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 g) as an amorphous material. 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; HPLC retention time: 4.450 min (Method: Same as for Step 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:26](=[O:40])([O:28][CH2:29][CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH2:31][NH2:32])[NH2:27]>>[C:26](=[O:40])([O:28][CH2:29][CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[CH2:31][NH:32][C:23](=[O:24])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[NH2:27]
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: NCC(COC(N)=O)c1ccccc1Cl
Product: NC(=O)OCC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1Cl

Procedure:
Analogously to the procedure of Example 63, 49 mg (135 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 156A in WO 2007/134862] were reacted with 34 mg (149 μmol) of the compound of Example 15A. This gave 27 mg (35% of theory) of the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[C:18]([CH:21]1[CH2:23][CH2:22]1)([CH3:20])[CH3:19])(=O)OC.O.[NH2:26][NH2:27]>C(O)(C)C.CCCCCCC>[CH:21]1([C:18]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:27][N:26]=2)([CH3:20])[CH3:19])[CH2:23][CH2:22]1
Reactant: NN
Reactant: COP(=O)(CC(=O)C(C)(C)C1CC1)OC
Reactant: O=C1C(=O)C2CCC1C2
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(c1cc2c(nn1)C1CCC2C1)C1CC1

Procedure:
white solid. MS (ESI): 229.2 (MH+). Prepared from bicyclo[2.2.1]heptan-2,3-dione, (3-cyclopropyl-3-methyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate. Submission of the racemate to preparative HPLC, using a chiral column, Chiralpak AD, with 5% isopropanol/heptane as eluant gave the two enantiomers, in optically pure form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:40][CH:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)[N:3]=1
Reactant: CCc1ccc(F)cc1C(=O)c1cnc(S(=O)CC)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(2-ethyl-5-fluoro-phenyl)-methanone (Example 202) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H5N5O3SF [(M+H)+] 422.1660, observed 422.1657.