Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 5 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and piperidine as starting materials, 12 mg (5%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.50 (s, 2 H) 2.30 (m, 4 H), 1.80 (m, 2 H), 1.55 (m, 4 H), 1.40 (m, 2 H); ES-MS m/z 514.04 [M+H]+, HPLC RT (min) 2.34.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[OH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([CH2:25][C:26](O)=[O:27])=[CH:19][C:18]=1[O:29][CH3:30].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([O:23][CH3:24])[C:17]([OH:16])=[C:18]([O:29][CH3:30])[CH:19]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1O
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(OC)c1O
Yield: 28.8 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a) (376 mg, 1.7 mmol), 2-(4-hydroxy-3,5-dimethoxyphenyl)acetic acid (350 mg, 1.7 mmol), PyBop (1 g, 2 mmol) and triethylamine (605 mg, 6 mmol) were stirred together in DMF (10 mL) at room temperature for 2 hours. The reaction mixture was diluted with aqueous 1N HCl (100 mL) and extracted with DCM (3×, 75 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated on the rotovap. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-(4-hydroxy-3,5-dimethoxyphenyl)acetamide (189 mg, 29%) as a white solid. 1H NMR (CDCl3, 400 MHz) 2.10 (s, 3H), 2.36 (s, 3H), 3.40 (s, 2H), 3.70 (s, 6H), 5.07 (s, 2H), 6.53 (s, 2H), 7.39 (s, 1H), 7.92 (s, 1H), 8.18 (s, 1H), 10.03 (s, 1H). LC/MS; [M+H] calculated for C, 19; H, 22; N, 4; O, 5; expected 387.16; found 387.6. Melting point: 187-188° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][CH:19]([C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:39][NH2:40]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([C:23]([F:24])([F:26])[F:25])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:40][N:39]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CC(C(=O)NCc3ccccc3)CCC2C(F)(F)F)n1
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
To a solution of 1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-(phenylmethyl)-6-(trifluoromethyl)-3-piperidinecarboxamide (66 mg, 0.129 mmol) in ethanol (2 mL) into a 5 mL microwave vial was added hydrazine monohydrate (0.121 mL, 3.86 mmol). The reaction was capped and heated overnight. Since the reaction was not completed, additional 50 uL of hydrazine monohydrate was added and heated overnight. The reaction was concentrated then re-dissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (35 mL/min, 25% CH3CN/H2O, 0.1% TFA to 50% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced under vacuum until most of the CH3CN was removed. Saturated aqueous NaHCO3 (10 mL) was added, and the resulting mixture was extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting material was transferred into a vial and water was added and freeze dried overnight to afford the title compound (27 mg) as a light yellow solid. LC-MS (ES) m/z=525 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.81-1.88 (m, 3H), 2.06-2.14 (m, 1H), 2.43-2.49 (m, 1H), 2.84 (bs, 3H), 3.14 (bs, 1H), 4.20-4.43 (m, 2H), 5.40 (s, 2H), 6.80 (bs, 1H), 7.22-7.31 (m, 3H), 7.31-7.38 (m, 2H), 7.62-7.69 (m, 1H), 7.71-7.75 (m, 1H), 8.02 (bs, 1H), 8.54 (t, J=5.9 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][C:27]=1[C:33]([F:34])([F:35])[F:36])#[N:30]
Reactant: N#Cc1ccc(NN)cc1C(F)(F)F
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1C(F)(F)F

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate (Preparation 31; 286 mg, 1.0 mmol) and 4-hydrazinyl-2-(trifluoromethyl)benzonitrile hydrochloride (Preparation 3; 298 mg, 1.3 mmol) according to Method B and Method C. The title compound was largely present as a mixture of cis and trans diastereomers:
Reaction SMILES: [N:1]1(C(N2C=CN=C2)=O)[CH:5]=CN=[CH:2]1.[Br:13][C:14]1[C:15]([C:19]([OH:21])=O)=[N:16][NH:17][CH:18]=1.CNC>C(Cl)Cl.C1COCC1>[Br:13][C:14]1[C:15]([C:19]([N:1]([CH3:5])[CH3:2])=[O:21])=[N:16][NH:17][CH:18]=1
Reactant: O=C(O)c1n[nH]cc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1n[nH]cc1Br
Reaction time: 8 h
Yield: 45.8 %

Procedure:
di(imidazol-1-yl)methanone (1910 mg) was added portionwise to a suspension of 4-bromo-1H-pyrazole-3-carboxylic acid (900 mg) in DCM (18 ml).After 2 hours dimethylamine 2M in THF (9.42 ml) was added portionwise and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-bromo-N,N-dimethyl-1H-pyrazole-3-carboxamide (471 mg) as a solid. NMR Spectrum: (DMSOd6): 2.95 (s, 3H), 2.98 (s, 3H), 7.99 (s, 1H); Mass spectrum: M+H+ 220.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:47])[O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:47])[O:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOc1ccc(OC(=O)Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: CCOc1ccc(OC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Ethoxyphenyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (41 mg, 0.14 mmol) and 4-ethoxyphenyl carbonochloridate (22.6 mg, 0.14 mmol) according to General Procedure H to give 50 mg (78.3%) of white solid. Anal. Calcd. for C27H35N5O2 m/z 461.3, found: 462.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.41 (d, J=9 Hz, 2H), 7.28 (q, J=3.0 Hz, 2H), 6.92 (d, J=9 Hz, 2H), 6.8 (d, J=9 Hz, 2H), 5.97 (d, J=7.8 Hz, 1H), 3.95 (q, J=7.0 Hz, 2H), 3.88 (d, J=11.4 Hz, 1H), 3.77 (d, J=13 Hz, 1H), 3.25 (m, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.39 (m, 2H), 1.88 (m, 3H), 1.68 (m, 1H), 1.61 (m, 3H), 1.47 (m, 1H), 1.30 (t, J=7.0 Hz, 3H), 1.2 (m, 4H), 1.11 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:37])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:37][C:15]([C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])[CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Yield: 97.2 %

Procedure:
7.6 g (29 mmol) of 4'-trifluoromethyl-biphenyl-2-carboxylic acid, 7.1 g (29 mmol) of 6-amino-3,4-dihydro-1H-isoquinoline-2-caboxyiic acid tert-butyl ester, 100 mg of DMAP and 6.1 g (32 mmol) of EDCl were mixed in 130 ml of methylene chloride for 12 hrs. Reaction was extracted with 2×150 ml 1N HCl, 2×150 ml 1N NaOH, 150 ml water, brine and concentrated to yield 14 g of a beige foam.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[C:31]([Cl:32])=[CH:30][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:20][CH2:19]2)=[O:15])=[C:12]([O:33][CH3:34])[CH:11]=1.[BH4-].[Na+].O>C(O)C>[NH2:9][C:10]1[C:31]([Cl:32])=[CH:30][C:13]([C:14]([NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:22][CH2:23]2)=[O:15])=[C:12]([O:33][CH3:34])[CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Yield: 72 %

Procedure:
Benzaldehyde (0.76 g) was added to a solution of 4-amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2.0 g) in ethanol (50 ml), and the mixture was stirred at refluxing temperature for 3 hr. Sodium borohydride (0.53 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:ammonia=50:5:1) to give 1.78 g of 4-amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccccn2)cc1
Solvent: CCO
Product: Nc1ccc(C(O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
In ethanol (50 ml) was dissolved (4-nitrophenyl)-(2-pyridyl)methanol (2.30 g), and to the mixture was added dried 10% palladium on carbon (0.12 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 19 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give (4-aminophenyl) (2-pyridyl)methanol (1.90 g) as pale yellow crystals.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29](O)=[O:30])=[CH:23]2>>[CH2:12]([C@H:3]([NH:2][C:29]([C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([Cl:19])=[CH:28][CH:27]=2)=[O:30])[C:4](=[O:5])[N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-phenyl-1-thiomorpholin4-yl-propan-1-one hydrochloride (2.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (2.6 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid first, then base). The crude product was then triturated with 1:1 ether-hexanes and dried. Yield 1.03 g, 94%; HPLC (60/40) 8.74 minutes (99%); PBMS 428/430 (MH+, 100%);
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[C:22]([O:27][CH:28](Cl)[CH3:29])(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][C@H:28]([O:27][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH3:29])=[O:19])[CH2:15]1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(Cl)OC(=O)C(C)C
Product: C=CCOC(=O)N1COC(=O)[C@]12C1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O[C@@H](C)OC(=O)C(C)C
Yield: 15.5 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 1.43 g) and 1-chloroethyl isobutyrate (1.80 g) were treated in the same manner as in Example A-1 (3) to give (1S,2S,3S,5R,6S)-3′-allyl 6-(1-(isobutyryloxy)ethyl) 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (A-8-1, 307 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>CCCCO>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Reactant: NCCO
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 60 %

Procedure:
225 mg of 6-chloro-N-(4-phenoxyphenyl)pyrimidin-4-amine, 82 mg of ethanolamine and 173 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC purification (EtOAc:EtOH=10:1). 2-(6-(4-Phenoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:18]([Br:17])=[CH:19][CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(Br)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-bromobenzoic acid
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1>CC(C)=O>[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:5][C:3](=[NH:6])[CH3:4])=[O:15])=[CH:9][CH:8]=1
Reactant: CC(=N)N
Reactant: Cc1ccc(N=C=O)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(=N)NC(=O)Nc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 23 but using 4.6 g. sodium in 500 ml. dry acetone, 18.8 g. acetamidine hydrochloride and 26.6 g. 4-tolyl isocyanate in 120 ml. of dry acetone, there was obtained after recrystallization from isopropyl alcohol 27.1 g. 1-(4-tolyl)-3-(acetimidoyl) urea hydrochloride; m.p. 210°-212°C.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1)CCC.Br[C:55]1[CH:68]=[CH:67][C:66]2[O:65][C:64]3[C:59](=[CH:60][C:61]([O:69][CH3:70])=[CH:62][CH:63]=3)[C:58](=[O:71])[C:57]=2[CH:56]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:70][O:69][C:61]1[CH:62]=[CH:63][C:64]2[O:65][C:66]3[C:57](=[CH:56][C:55]([C:40]4[CH:45]=[N:44][CH:43]=[N:42][CH:41]=4)=[CH:68][CH:67]=3)[C:58](=[O:71])[C:59]=2[CH:60]=1
Reactant: COc1ccc2oc3ccc(Br)cc3c(=O)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncnc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2oc3ccc(-c4cncnc4)cc3c(=O)c2c1
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A vial charged with Pd2(dba)3 (0.150 g, 0.164 mmol), XPhos (0.391 g, 0.819 mmol), 5-(tributylstannyl)pyrimidine (1.81 g, 4.92 mmol), 2-bromo-7-methoxy-9H-xanthen-9-one (1.000 g, 3.28 mmol) and dioxane (10 mL). The reaction mixture was evacuated and backfilled with nitrogen. The reaction mixture was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with water and EtOAc. A grey solid precipitated out, which was filtered off. The solid was washed with EtOAc and water. The grey solid dried under reduced pressure to afford 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one) (0.600 g, 60.2% yield). Step 2: A solution of vinylmagnesium chloride (1.6M solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF (10 mL) at −78° C. After 30 min, the reaction mixture was allowed to warm to −10° C. and was then quenched with saturated aqueous ammonium chloride. The reaction was extracted with EtOAc, and the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow gum. Step 3: 2 N HCl (3 mL) was added to solution of 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol (50 mg, 0.150 mmol) and thiourea (9.25 μL, 0.171 mmol) in HOAc (5 mL). The reaction mixture was allowed to stir overnight at rt and concentrated under reduced pressure. The residue was treated with of TFA (4 mL). The reaction mixture was stirred overnight at rt. The reaction mixture was concentrated under reduced pressure and the residue was treated with aqueous, half-saturated sodium bicarbonate, extracted with EtOAc, and concentrated under reduced pressure. The residue was purified by chromatography (DCM/MeOH 20:1 to 5:1) to give 2′-methoxy-7′-(pyrimidin-5-yl)-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[CH:24]1([CH2:27][OH:28])[CH2:26][CH2:25]1>C(O)C>[CH:24]1([CH2:27][O:28][C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([CH:2]=[O:3])[CH:7]=3)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[N:10]=2)[CH2:26][CH2:25]1
Reactant: OCC1CC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(OCC2CC2)c2cc(C=O)ccc21

Procedure:
The title compound was prepared in close analogy to the procedure described in Example 11A using 166 mg (0.372 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 4 ml cyclopropylmethanol (instead of ethanol). The reaction mixture was filtered, and the filtrate was purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to afford 53 mg (57% of th.) of the title compound.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1.O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]3[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]3)=[N:18]2)=[CH:13][CH:12]=1
Reactant: CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccc(F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 104 %

Procedure:
To a stirred mixture of cyanogen bromide (21.67 g, 0.204 moles) and potassium carbonate (33.2 g, 0.24 moles) in dimethyl sulfoxide (400 ml) was added dropwise a solution of 1-(4-fluorophenyl)-3-(1-methyl-4-piperidinyl)-1H-indazole (59.45 g, 0.192 moles), the free base of example 67, in hot dimethyl sulfoxide (375 ml). The reaction was stirred at ambient temperature for 4 days and then poured into H2O (500 ml). The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 64 g of a solid. The product was recrystallized twice from isopropyl alcohol yield 35.7 g (58%) of 4-[1-(4-fluorophenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile, mp 108°-110° C.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:10][N:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[N:13]=[CH:12]1>>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[N+:7]([O-:9])=[O:8])[N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Product: Cn1cnc(-c2sccc2[N+](=O)[O-])c1
Temperature: 95 °C

Procedure:
The title compound was prepared from 2-chloro-3-nitrothiophene (2.57 g, 15.7 mmol) and 1-methyl-4-(tributylstannyl)-1H-imidazole (8.64 g, 23.3 mmol) using protocol E except the reaction was heated to 90° C. (rather than 95° C.) and was purified by flash chromatography (hexane:ethyl acetate). Method [1] Retention time 0.57 min by HPLC (MH+ 210).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[F:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[F:24])=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccccc1F
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccccc3F)(CC1)CC2
Yield: 23.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-fluoroaniline (38.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-fluorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.2 mg).