Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(I)C=CC=1NC1N2C=NC=C2C=NC=1C(O)=O.C[O:23][C:24]([C:26]1[N:27]=[CH:28][C:29]2[N:30]([CH:41]=[N:42][CH:43]=2)[C:31]=1[NH:32][C:33]1[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][C:34]=1[F:40])=[O:25]>>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:31]2[N:30]3[CH:41]=[N:42][CH:43]=[C:29]3[CH:28]=[N:27][C:26]=2[C:24]([OH:25])=[O:23])=[C:34]([F:40])[CH:35]=1
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Agent: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Product: O=C(O)c1ncc2cncn2c1Nc1ccc(Br)cc1F

Procedure:
The desired compound was prepared in an analogous fashion to 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid, using 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester as the starting material. LCMS (method D1): RT=0.713 min, [M+H]+=351/353.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](O)(=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:33])/[CH:25]=[CH:26]/[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)/C=C/c4ccccc4)nc3cc21

Procedure:
(E)-N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-phenyl-acrylamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and cinnamoic acid (131 mg, 0.89 mmol). The title compound was obtained as yellow powder (86 mg, 24%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[C:4]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:5][C:6]2[C:11]([CH:2]=1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCNc1nc2cccnc2cc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
The preparation of 4-chloro-3-nitro[1,5]naphthyridine is described in Part A of Example 1. Ethyl 4-aminobutyrate hydrochloride (9.6 g, 57.3 mmol, 1.2 eq) was added to a suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol, 1.0 eq) in dichloromethane (200 mL) and stirred at 5° C. Triethylamine (16.6 mL, 119.3 mmol, 2.5 eq) was added and the reaction mixture was stirred for 2 hours and allowed to warm to ambient temperature. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The phases were separated and the combined aqueous layers were extracted with chloroform (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.5 g of ethyl 4-[(3-nitro[1,5]naphthyridinyl)amino]butyrate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(Cl)c(Cl)c1
Yield: 23 %

Procedure:
The title compound was synthesized from methyl 4-(3,4-dichlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.064 g, 0.2 mmol) and lithium hydroxide (0.084 g, 2.0 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford a light brown solid: 14 mg, 23% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.00-2.15 (m, 1H), 2.46-2.67 (m, 3H), 2.69-2.84 (m, 2H), 3.19-3.29 (m, 1H), 6.31 (s, 1H), 7.11 (dd, J=8.20, 2.00 Hz, 1H), 7.34 (d, J=1.95 Hz, 1H), 7.37-7.45 (m, 1H); HPLC (UV=96.1%), (ELSD=100%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][S:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH2:17]([N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]1[S:6][CH2:5][C:4]([OH:24])=[O:3])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CSC1c2ccccc2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)CSC1c2ccccc2C(=O)N1Cc1ccccc1
Yield: 41.7 %

Procedure:
To a solution of compound 17 (8 gm, 24.5 mmol) in methanol (64 mL) and water (16 mL) at room temperature was added potassium carbonate (5.7 gm, 41.6 mmol) and the resulting reaction mixture was allowed to stir at reflux for 3 hours. The reaction mixture was poured onto 1N HCl and extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were filtered and the filterate dried over anhydrous sodium sulfate and concentrated in vacuo to provide 3.2 gm of 18 as a pale pink solid (7.8 gm, 41% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26](=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J11) (240 mg. 0.75 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example L9) (215 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (245 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:7][CH:6]=2)=[C:12]2[N:13]=[C:14]([CH3:23])[N:15]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:16](=[O:17])[C:11]2=[N:10]1
Reactant: CN(C)C=O
Reactant: Cc1nc2c(-c3ccc(Br)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc2c(-c3ccc(C#N)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 200 °C

Procedure:
A mixture of 3-(4-bromophenyl)-2-(2-chlorophenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-9, 109 mg, 0.23 mmol), Zn(CN)2 (29 mg, 0.25 mmol), Pd(PPh3)4 (6.8 mg, 5.9 μmol) in DMF (2.5 ml) was heated in a microwave apparatus (Emrys Optimizer, Personal Chemistry) at 200° C. for 10 minutes. The reaction mixture was quenched with saturated aqueous NaCl, filtered, and extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4) and concentrated under vacuum. The crude residue was purified on a Chromatotron using 1 mm plates and a solvent gradient of 33% EtOAc/hexanes to 50% EtOAc/hexanes to give the desired product, 4-[2-(2-chlorophenyl)-5-methyl-7-oxo-6-(2,2,2-trifluoroethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-3-yl]-benzonitrile (5A-1), as an amorphous solid (145 mg): MS (m/z) 444.4 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.63–7.53 (m, 5H), 7.52–7.42 (m, 3H), 5.00–4.80 (br m, 2H), 2.66 (s, 3H).
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[C:12](N)[C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])([O-:7])=[O:6].[ClH:17]>O.[Cu]Cl>[Cl:17][C:12]1[CH:14]=[C:8]([N+:5]([O-:7])=[O:6])[C:9]([CH3:16])=[CH:10][C:11]=1[CH3:15]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1Cl
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of sodium nitrite (7.2 g, 0.1 mol) in water (20 mL) was added dropwise over 45 min at <5° C. to a stirred suspension of 5-nitro-2,4-xylidine (16.6 g, 0.1 mol) in conc. hydrochloric acid (300 mL). After complete addition the reaction was stirred at <5° C. for 1 h then a solution of copper(I)chloride (16.0 g, 0.16 mol) in conc. hydrochloric acid (50 mL) was added dropwise over 20 min at <5° C. (CARE: effervescence at first). The reaction was then warmed from 0° C. to room temperature and stirred for 18 h. The mixture was then carefully poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography (SiO2; heptane) to give the product as a yellow oil (8.8 g, 47%). IR νmax (film)/cm−1 3103, 2985, 2935, 2863, 2744, 2432, 1610, 1572, 1518, 1480, 1454, 1384, 1346, 1286, 1266, 1244, 1197, 1166, 1157, 1107, 1036, 982, 894, 842, 759, 746, 725, 704, 646 and 602; NMR δH (400 MHz; CDCl3) 8.01 (1H, s), 7.20 (1H, s), 2.56 (3H, s), 2.41 (3H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C:41]([CH3:46])([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:46][C:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:45])[C:42]([NH:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:43]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 90.6 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (400 mg) and 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (215 mg) were used, whereby the title compound (510 mg) was yielded.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:5](=[O:17])[NH:4][C:3]=1[C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1.CCN(C(C)C)C(C)C.[CH:40]1([N:45]=[C:46]=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH:40]1([NH:45][C:46]([N:4]2[C:3]([C:18]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=4)[CH:20]=[CH:21][N:22]=3)=[C:2]([CH3:1])[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[C:5]2=[O:17])=[O:47])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=C=NC1CCCC1
Reactant: Cc1c(-c2nccn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2nccn2-c2ccc(C#N)cc2)n(C(=O)NC2CCCC2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
4-[5′-Methyl-2′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,3′-dihydro-1′H-[2,4′]biimidazolyl-1-yl]-benzonitrile (Example 59, 108 mg, 0.26 mmol) was suspended in dry DCM (5 ml) and DIPEA (130 μl, 3 eq.) was added followed by cyclopentyl isocyanate (90 μl, 88 mg, 0.79 mmol). The mixture was heated and stirred at 45° C. for 24 h. The solvent was removed in vacuo and the residue purified by chromatography eluting with EtOAc, thereby yielding the title compound (100 mg, 73%).
Reaction SMILES: OS(O)(=O)=O.[BrH:6].[NH2:7][C:8]1[C:9]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[C:10]([CH2:13][CH2:14][CH2:15]O)[NH:11][N:12]=1.[OH-].[Na+]>>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:9]1[C:10]([CH2:13][CH2:14][CH2:15][Br:6])=[N:11][NH:12][C:8]=1[NH2:7]
Reactant: Nc1n[nH]c(CCCO)c1-c1nc2ccccc2s1
Reactant: Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1[nH]nc(CCCBr)c1-c1nc2ccccc2s1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of concentrated H2SO4 (3 mL) and hydrobromic acid (6 mL of 48%) was added 3-(5-amino-4-benzothiazol-2-yl-2H-pyrazol-3-yl)-propan-1-ol (810 mg, 3.0 mmol). The resulting mixture was refluxed for 2 hrs. The mixture was cooled to room temperature, poured into ice water, and adjusted to pH 3-4 using 5% NaOH solution. The resulting sticky solid was isolated by filtration, washed with water and air-dried to yield 815 mg (80%) of 4-benzothiazol-2-yl-5-(3-bromopropyl)-2H-pyrazol-3-ylamine as a cream coloured solid. The crude material was used in the subsequent step without further purification. MS (m/z, ES+): 337.1 (Br79M+1, 61%), 339.1 (Br81M+1, 59%), 257.2 (M-HBr, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[CH:8]([NH2:10])[CH3:9]>O.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9]
Reactant: CC(N)c1nc2ccn(C)c2cc1Br
Solvent: O
Solvent: CC(C)O
Product: C[C@H](N)c1nc2ccn(C)c2cc1Br
Temperature: 42.5 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
Ortho-chloro-D-tartranilic acid (i.e., (2S,3S)-4-((2-chlorophenyl)amino)-2,3-dihydroxy-4-oxobutanoic acid) (177.5 g, 683.6 mmol) was suspended in water (367 mL) and isopropanol (1.43 L). The mixture was warmed to 40-45° C. over a period of 10 minutes. A solution of 1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (170 g, 669 mmol) in IPA was added slowly over a period of 10 minutes while maintaining the temperature of the reaction mixture at 35-45° C. The transfer vessel was rinsed with IPA (100 mL). The IPA rinse was added to the reaction mixture, which was then warmed to 80-85° C. and stirred at this temperature for 15 minutes. The mixture was cooled to 70-75° C. over a period of 30 minutes and a seed of ortho-chloro-D-tartranilic acid salt of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (350 mg) was added. The reaction mixture was maintained at 70-75° C. for an additional 20 minutes before cooling the mixture to 60-65° C. over a period of 45 minutes. The reaction mixture was maintained at 60-65° C. with stirring for 2 hours before slowly cooling the mixture to 20° C. over a period of 9 hours. The mixture was stirred for 8 hours at 20° C. and then filtered. The solid product was washed with IPA/water (9:1 v/v, 2×510 mL) and then re-suspended in IPA/water (9:1 v/v, 1.19 L). The mixture was warmed to 40-45° C. and maintained at this temperature for 2 hours. The suspension was slowly cooled to 20° C. over a 1 hour period and maintained at 20° C. for 1.5 hours. The reaction mixture was filtered, washed with IPA/water (9:1 v/v, 595 mL), and dried under vacuum at 40° C. to give ortho-chloro-D-tartranilic acid salt of the title compound as a white solid (115.3 g, 99.1% de, 99.6% purity by HPLC).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][CH2:15][CH2:14][NH:13]2)=[C:7]([CH3:17])[CH:6]=1)=[O:4].[ClH:18]>>[ClH:18].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:13][CH2:14][CH2:15][NH:16]2)=[C:7]([CH3:17])[CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(N=C2NCCN2)c(C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)ccc1N=C1NCCN1
Temperature: 75 °C

Procedure:
2-(4-Methoxycarbonyl-2-methylphenylimino)imidazolidine (2.0 g from Example 4) is dissolved in 4 N hydrochloric acid (30 ml) and heated at 75° C. for 18 hours. After cooling crystals separate which are filtered (2.2 g). Recrystallization from water gives 2-(4-carboxy-2-methylphenylimino)imidazolidine hydrochloride, m.p. 280°-281° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)OCCO1.CO.Cl.C([BH3-])#N.[Na+]>C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[N:19]1[CH2:20][CH2:21][CH2:22][CH:23]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(N1CCc2ccc(Cl)c(NCCCC3(c4ccccc4)OCCO3)c2CC1)C(F)(F)F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(N1CCc2ccc(Cl)c(N3CCCC3c3ccccc3)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[3-(2-phenyl-[1,3]dioxolan-2-yl)-propylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.78 g, 5.76 mmol) in DCM (25 mL) and add methanol (1 mL) and 2 N HCl in diethyl ether (25 mL) and stir at RT for 16 h. Concentrate and dissolve the residue in acetic acid (30 mL) and add sodium cyanoborohydride (1.81 g, 28.78 mmol). Stir the reaction at RT for 1 h then concentrate. Dissolve the residue in EtOAc (500 mL) and extract with saturated sodium bicarbonate solution (500 mL). Extract the aqueous layer with EtOAc (100 mL) and combine the organic fractions, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 EtOAc:hexanes) to give the title compound as a foam (1.72 g, 71%).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C>[CH2:5]([N:12]1[CH2:17][CH2:16]/[C:15](=[N:3]\[N:2]([CH3:4])[CH3:1])/[CH:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CN(C)N
Solvent: CCO
Product: CC1CN(Cc2ccccc2)CC/C1=N\N(C)C

Procedure:
N,N-dimethylhydrazine (3 ml, 39.3 mmol) and 1-benzyl-3-methyl-piperidin-4-one (4 g, 19.7 mmol) are dissolved in 50 ml of ethanol and refluxed for 18 hours. The reaction mixture is evaporated under reduced pressure and dried at high vacuum.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=[O:19])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:31][C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[C:33]=1[Cl:41]>C1COCC1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:31][C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[C:33]=3[Cl:41])[C:14]2=[O:19])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCCC2=O)CC1
Reactant: Clc1c(CBr)sc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3sc4ccccc4c3Cl)C2=O)CC1
Reaction time: 0.08 h

Procedure:
Place trans-1-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-piperidin-2-one, (300 mg, 0.96 mmol) in 7.0 mL of THF, cool to −78° C. and treat with 2.0 M LDA (0.72 mL, 1.5 mmol). Stir for 5.0 minutes, treat with 2-bromomethyl-3-chloro-benzo[b]thiophene (375 mg, 1.5 mmol) and stir overnight at room temperature. Quench reaction with ammonium chloride, extract with dichloromethane, dry over sodium sulfate and purify via silica chromatography (ethyl acetate/hexanes 0-25%) affords 310 mg (65
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:63](O)(=[O:67])[CH:64]([CH3:66])[CH3:65]>CN(C=O)C>[C:63]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)(=[O:67])[CH:64]([CH3:66])[CH3:65]
Reactant: CC(C)C(=O)O
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A vial was charged with (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (32 mg, 0.076 mmol), HATU (58 mg, 0.15 mmol) and N-methylmorpholine (33 μL, 0.30 mmol) in DMF (2.0 mL). Isobutyric acid (8.5 μL, 0.091 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((6-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.36 (21 mg) as the trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[CH2:8]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([O:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@@H:9]([C:20]([O:22][CH3:23])=[O:21])[CH2:8]1)(=[O:4])=[O:3]
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
MsCl (6.61 mL, 85 mmol) was added dropwise at 0° C. to a solution of (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypiperidine-1,2-dicarboxylate (21 g, 81 mmol) and DMAP (100 mg, 0.81 mmol) in pyridine (50 mL). The mixture was stirred at room temperature for 5 hours and then was concentrated under reduced pressure to remove most solvent. Brine (200 mL) was added and extracted with ethyl acetate (2×200 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give title compound 26.7 g (98%) as colorless oil. LC-MS: 338.1 (t=1.9 min).