Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@@H:5]([NH2:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[NH2:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30](O)=[O:31].Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:26])[C@@H:5]([NH:25][C:30](=[O:31])[C:29]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:28]=1[NH2:27])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OCc2ccc(C(C)(C)C)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 62 %

Procedure:
(S)-2-(2-Amino-5-chloro-benzoylamino)-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester (175 mg) was prepared from (S)-2-amino-3-[4-(4-tert-butyl-benzyloxy)-phenyl]-propionic acid methyl ester-hydrochloride (214 mg, 0.57 mmol) and 2-amino-5-chloro-benzoic acid (101 mg) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 5 mL of 1N HCl and 5 mL of EtOAc. The organic layer was washed with 1N HCl, saturated sodium bicarbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM).
Reaction SMILES: ClC(OCC)=O.[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2.C(N(CC)CC)C.[BH4-].[Na+].Cl>O1CCCC1.O>[CH3:7][C:8]1([CH3:31])[CH2:17][CH2:16][C:15]([CH3:18])([CH3:19])[C:14]2[CH:13]=[C:12]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C(=O)O)cc3)ccc21
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(CO)cc3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A solution of 0.97 g (9 mmol) of ethyl chloroformate in 5 ml of tetrahydrofuran was added dropwise to a solution of 3 g (9 mmol) of 4-carboxybenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether and 0.9 g (9 mmol) of triethylamine in 20 ml of dry tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 30 min, the solid was filtered off, and the filtrate was added dropwise to a solution of 0.83 g (22 mmol) of sodium borohydride in 8 ml of tetrahydrofuran and 8 ml of water. The reaction mixture was then allowed to reach room temperature within 1 h and was then acidified with 1N hydrochloric acid. Most of the tetrahydrofuran was removed in a rotary evaporator, and the remaining aqueous phase was extracted with chloroform. The organic phase was dried over Na2SO4 and concentrated. Fractional crystallization from ethyl acetate, discarding the first fraction, resulted in 1.1 g of the title compound of melting point 108°-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:10])=[CH:4][C:3]=1[C:16]1[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][CH:17]=1.[C:24]([C:26]1[N:27]=[C:28]([C:39]([O-])=[O:40])[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=1)#[N:25].[K+].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][C:19]1([CH3:23])[CH2:20][CH2:21][C:16]([C:3]2[CH:4]=[C:5]([CH2:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:2]=2[NH:1][C:39]([C:28]2[N:29]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:30]=[C:26]([C:24]#[N:25])[N:27]=2)=[O:40])=[CH:17][CH2:18]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(CC(=O)NCCCO)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-N-(3-hydroxy-propyl)-acetamide (as prepared in the previous step), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 1, step (d)), PyBroP and DIEA according to the procedure in Example 1, step (f). 1H-NMR (CDCl3; 400 MHz): δ 9.74 (s, 1H), 8.31 (d, 1H, J=8.3 Hz), 7.78 (s, 1H), 7.20 (dd. 1H, J=8.4, 1.9 Hz), 7.11 (d, 1H, J=1.9 Hz), 7.03 (br s, 1H), 5.94 (s, 2H), 5.75 (s, 1H), 4.22 (t, 1H, J=6.1 Hz), 3.67-3.63 (m, 2H), 3.61-3.56 (m, 2H), 3.52 (s, 2H), 3.38-3.33 (m, 2H), 2.27-2.23 (m, 2H), 2.08-2.07 (m, 2H), 1.67-1.61 (m, 2H), 1.57 (t, 2H, J=6.2 Hz), 1.09 (s, 6H), 0.98-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C[O:20][C:21](=[O:34])[CH2:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([SH:32])=[CH:26][C:25]=1[CH3:33]>>[CH3:31][O:30][C:28]1[C:27]([S:32][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH:8]=2)=[CH:26][C:25]([CH3:33])=[C:24]([CH:29]=1)[O:23][CH2:22][C:21]([OH:34])=[O:20]
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 48B and 1D. MS m/z 477 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[C:33]([O:41][CH3:42])=[N:32]1)=O)(C)(C)C.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.N.[OH-].[Na+].[NH4+].[Cl-]>C(O)(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:40][C:36]4[CH:35]=[C:34]5[C:39](=[CH:38][CH:37]=4)[NH:31][N:32]=[C:33]5[O:41][CH3:42])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: N
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc12
Temperature: 85 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (48.2 mg, 0.144 mmol) and 5-amino-3-methoxyindazole-1-carboxylic acid tert-butyl ester (40.4 mg, 0.153 mmol) in isopropyl alcohol (3.0 mL) in a sealed tube was heated to 85° C. (bath temp.) for 16 h. LC/MS at that time showed the product (minor), indazole-Boc-product (major), de-Boc product (minor), and both starting materials. The bath temperature was increased to 90° C., and heating was continued for 2 d. After reaching rt, di-tert-butyldicarbonate (15 mg, 0.069 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) were added to the reaction mixture, and the now clear solution was stirred at rt for 2 h. LC/MS at that time indicated complete conversion of the de-Boc product to the product. 14.8 M of ammonia in Water (2.0 mL) was added, and the mixture was stirred at rt overnight and heated to 90° C. for 5 h. Sodium hydroxide (6.5 mg, 0.16 mmol) was added, and heating was continued overnight. Water and sat. NH4Cl solution were added, the mixture was extracted with CH2Cl2 (100 mL) and CH2Cl2:MeOH 10:1 (50 mL), and the combined organic layers were dried over MgSO4. The organic solution was filtered through a plug of silica gel (≈1″ in a 60 mL glass frit), which was further washed with 5% MeOH in CH2Cl2 until the entire product was eluted. The solution containing the product was concentrated and dried overnight in vacuo. The solid from the aqueous phase was filtered off, washed with water, and dried in vacuo overnight. From the precipitate of the aqueous phase, one obtained the title compound as light brown solid. From the silica gel plug filtration, one obtained a light brown solid that was further purified by MDP to give the title compound as off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.44 (s, 9H), 2.42-2.50 (brs, 2H), 3.52-3.60 (m, 2H), 4.00 (s, 3H), 3.98-4.07 (m, 2H), 6.38 (brs, 1H), 6.75 (brs, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.62 (dd, J=2.0, 8.8 Hz, 1H), 8.25 (s, 1H), 8.26 (s, 1H), 9.29 (s, 1H), 11.78 (s, 1H), 11.90 (s, 1H). MS (ES+): m/z 462.0 (100) [MH+]. HPLC: tR=2.5 min (ZQ2000, polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH:8]=1)C.[ClH:20]>C(#N)C>[ClH:20].[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)COc1cccc(Cc2ncc[nH]2)c1
Agent: Cl
Solvent: CC#N
Product: O=C(O)COc1cccc(Cc2ncc[nH]2)c1

Procedure:
Hydrolysis of 3-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester free base with concentrated hydrochloric acid according to the method of Example 7 gave 3-(1-imidazolylmethyl)phenoxyacetic acid hydrochloride, m.p. 179°-181° C. (from aqueous acetonitrile). Found: C, 53.23, H, 4.84, N, 10.65. C12H12N2O3.HCl requires: C, 53.64, H, 4.88, N, 10.43%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: Nc1ccc(F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)OCC
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-phenylamine (5.1 mL, 54.4 mmol) and diethyl ethoxymethylenemalonate (10 mL, 49.5 mmol) was heated at 100° C. for 4 hours, an oil which solidified on cooling. The solid was triturated in heptane, collected by filtration and washed with heptane, to give the product as a colorless solid, 10.5 g (75%). MS: m/z 282.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:19](=[O:20])[CH:18]3[CH:13]([CH2:14][CH:15]=[CH:16][CH:17]3[NH:21]C(=O)OC(C)(C)C)[C:12]2=[O:29])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][CH:17]1[CH:16]=[CH:15][CH2:14][CH:13]2[CH:18]1[C:19](=[O:20])[N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[C:12]2=[O:29]
Reactant: CC(C)(C)OC(=O)NC1C=CCC2C(=O)N(CCc3ccc(C#N)cc3)C(=O)C12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN2C(=O)C3CC=CC(N)C3C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.008 g (2.55 mmol) of tert-butyl 2-[2-(4-cyanophenyl)ethyl]-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylcarbamate are dissolved in 20 ml of dichloromethane, and 0.79 ml (10.2 mmol) of trifluoroacetic acid is added. After 4 h of stirring at room temperature, the reaction mixture is concentrated using a rotary evaporator and worked up using EtOAc and saturated aqueous NaHCO3 solution. The organic phase is dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The crude product is chromatographed on silica gel (CH2Cl2/EtOH=50/1+0.5% aqueous NH3 solution (25% strength)). This gives 530 mg (70% of theory) of the desired compound. MS=337 (M+H+MeCN), 296 (M+H), rt (Method 4)=2.04 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.C(OC(=O)C)(=O)C.P(=O)(O)(O)O>O>[CH2:7]1[CH2:8][C:9](=[O:11])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:6]1
Reactant: O=C(O)CCCc1cccs1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCc2sccc21
Yield: 88.9 %

Procedure:
4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in a round bottom flask with acetic anhydride (30 mL) and phosphoric acid (0.6 mL), and heated to reflux for 3.2 hours. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (22.60 g) which was vacuum distilled (1 mm Hg, 107-115° C.) to give a white solid (13.08 g, 51%): mp 34-40° C.); 1H NMR (CDCl3) 300 MHz 7.29 (d, J=5.2 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.13 (m, 2H). M+H=153.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:18]=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH3:22][C:23]([CH3:25])=O>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([N:18]=[C:23]([CH3:25])[CH3:22])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2N=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)=NN1CC(c2ccc(F)cc2)c2cc(C)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
3-(4-Fluorophenyl)-5-methyl-1-nitrosoindoline (1.2 g, 0.00468 mol) was dissolved in acetone (60 mL). To this was added saturated ammonium chloride solution (6.0 mL) and the reaction mixture was cooled to 0° C. Zinc dust (1.2 g, 0.0187 mol) was added portionwise over 30 min. at 0° C. After the addition, the reaction mixture was stirred for 1 h at RT. After completion of reaction (monitored by TLC), the reaction mixture was filtered through Celite, solvent was removed under reduced pressure and the residue purified by column chromatography (8% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (0.78 g, 60% yield).
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:7][NH:8]2)[CH:2]=[CH2:3].C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2[nH]cc(CCNC(=O)CC)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CCc1c(O)ccc2c1C(CCNC(=O)CC)CN2
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of N-[2-(4-allyl-5-hydroxyindol-3-yl)ethyl]propionamide (3.73 g, 14.3 mmol) in acetic acid (20 mL) was added sodium cyanoborohydride (2.7 g, 43.0 mmol) portionwise maintaining the reaction temperature around 15° C. The mixture was stirred for 1 hour maintaining the temperature 15 to 20° C. and then poured into water. The product was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, brine and water, dried over anhydrous magnesium sulfate and evaporated to afford the title compound. This compound was used for the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[O:13].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(OCC)C.O>CN(C)C=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH:5]=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[O:11][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]
Reactant: N#CCCCCCBr
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCCCC#N)ccc(C(=O)c2ccccc2O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 12.5 g of (2,4-dihydroxy-3-propylphenyl)(2-hydroxyphenyl)methanone in 460 ml of dimethylformamide were added 1.83 g of 60% sodium hydride in oil. The mixture was stirred for one hour under a nitrogen atmosphere. A solution of 4.9 ml of 6-bromohexanenitrile in a small volume of dimethylformamide was added. The reaction was stirred at 60° C. overnight, cooled to 25° C., and poured into a diethyl ether/water mixture. The layers were separated, and the organic layer was washed three times with water, dried over magnesium sulfate, filtered, and evaporated. Purification by high pressure liquid chromatography over silica gel eluting with a 15-35% ethyl acetate/hexane gradient, and evaporation of the desired fractions provided 6.1 g of the desired title product. Crystallization from ethyl acetate/hexane provided material with a melting point of 62°-63° C.
Reaction SMILES: [NH3:1].CO.[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH3:12])[N:6]=1>O1CCOCC1>[Cl:4][C:5]1[N:6]=[C:7]([CH3:12])[N:8]=[C:9]([NH2:1])[CH:10]=1
Reactant: N
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(N)cc(Cl)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Ammonia, 2.0 M in methyl alcohol (6.0 mL, 12 mmol) was added to a stirred yellow suspension of 4,6-dichloro-2-methylpyrimidine (Aldrich) (0.487 g, 3 mmol) in 1,4-dioxane (10.0 mL) at room temperature. The resulting mixture was sealed and stirred at 70° C. overnight. After cooling, the reaction mixture was concentrated and the crude residue was dissolved in DCM/MeOH and mixed with SiO2. The solvent was evaporated and the residue was purified by flash column chromatography (pure DCM to 10% MeOH in DCM) to give 6-chloro-2-methylpyrimidin-4-amine (0.25 g, 58%) as a white solid. MS (API-ES) m/z 144 (M+H)+.
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12]([CH2:14][CH3:15])[C:11]2[C:16]([CH3:19])=[N:17][S:18][C:10]=2[C:9]=1[OH:20])=[O:7])CCC.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH2:14]([C:12]1[C:11]2[C:16]([CH3:19])=[N:17][S:18][C:10]=2[C:9]([OH:20])=[C:8]([C:6]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:7])[N:13]=1)[CH3:15]
Reactant: CCCCOC(=O)c1nc(CC)c2c(C)nsc2c1O
Reactant: NCC(=O)O
Product: CCc1nc(C(=O)NCC(=O)O)c(O)c2snc(C)c12

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-ethyl-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and glycine: MS (m/z) 296.2 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:20]1([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[CH:27][C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[CH:31][CH:30]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(N5CCOCC5)cc4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-[2-(4-morpholin-4-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 4-morpholin-4-yl-phenylboronic acid following general procedures as described in these Examples. MP 233-235° C., M+H=405.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:61]1[CH2:66][CH2:65][CH:64]([N:67]2[CH2:73][CH2:72][C:71]3[CH:74]=[CH:75][CH:76]=[CH:77][C:70]=3[NH:69][C:68]2=[O:78])[CH2:63][CH2:62]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:61]4[CH2:62][CH2:63][CH:64]([N:67]5[CH2:73][CH2:72][C:71]6[CH:74]=[CH:75][CH:76]=[CH:77][C:70]=6[NH:69][C:68]5=[O:78])[CH2:65][CH2:66]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:29])[C:5]=2[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CCN2CCCCC2)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (54 mg, 0.123 mmol) was dissolved in N,N-dimethylformamide (1.5 ml). N,N-Diisopropylethylamine (100 μL, 0.574 mmol) was added to the mixture followed successively by TBTU (42 mg, 0.131 mmol) and then 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (43 mg, 0.175 mmol). Reaction stirred at room temperature for 4 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 54% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.85 (s, 1H) 8.50 (s, 1H) 7.32 (s, 1H) 6.96-7.11 (m, 3H) 6.80 (s, 1H) 5.26 (s, 2H) 4.44-4.54 (m, 1H) 4.27-4.37 (m, 1H) 4.06 (d, J=14.04 Hz, 1H) 3.79-3.96 (m, 2H) 3.34-3.44 (m, 2H) 3.05-3.25 (m, 3H) 2.82-3.02 (m, 4H) 2.45-2.66 (m, 2H) 2.28-2.40 (m, 1H) 2.04-2.26 (m, 4H) 1.80-1.95 (m, 2H) 1.58-1.73 (m, 2H) 1.40-1.57 (m, 1H) 1.18 (bs, 6H). High resolution MS m/e (M+H)+=666.2756.
Reaction SMILES: BrCC1C=CC(C(=O)CN2C(=O)C=C(OC[C:20]3[CH:25]=[CH:24][C:23](Cl)=[CH:22][N:21]=3)C=N2)=CC=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:54])[CH2:37][N:38]2[C:43](=[O:44])[CH:42]=[C:41]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=3)[CH:40]=[N:39]2)=[CH:32][CH:31]=1>>[F:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][O:45][C:41]2[CH:40]=[N:39][N:38]([CH2:37][C:36](=[O:54])[C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:20]4)=[CH:31][CH:32]=3)[C:43](=[O:44])[CH:42]=2)=[N:48][CH:49]=1
Reactant: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CBr)cc1
Reactant: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CCl)cc1
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CN2CCCCC2)cc1

Procedure:
The following examples are prepared as described for example 33.1 (Starting materials: either preparation 18d or 19d depending on substituent X). For example 33.6-33.10 3.0 eq of the corresponding amine are used.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1.N1C=CC=CC=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CC#N.O.CO.CS(C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([S:22]([NH:1][C:2]3[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=3)(=[O:24])=[O:23])=[C:19]([CH3:26])[C:18]=2[CH:27]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1nc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)sc1C(=O)O
Temperature: 60 °C
Yield: 24 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (9.3 mg, 0.050 mmol), 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (14 mg, 0.050 mmol) and pyridine (8 μL, 0.100 mmol) in MeCN (400 μL) was heated at 60° C. for 7 days. The solvent was removed and the residue redissolved in 1 M NaOH (300 μL, 0.300 mmol) and then heated at 60° C. over night. The crude product was diluted with water/MeOH/DMSO and acidified by addition of TFA. The product was purified by reversed phase chromatography (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 24% yield (4.9 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.47 (s, 3 H) 2.65 (s, 3H) 7.47 (dd, J=8.67, 2.08 Hz, 1 H) 7.88 (dd, J=8.67, 0.51 Hz, 1 H) 7.89 (dd, J=2.08, 0.51 Hz, 1 H). MS (ESI+) m/z 403 [M+H]+.