Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7]1.[CH3:18]O>>[ClH:3].[NH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCC1CCNCC1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCC1CCNCC1
Reaction time: 8 h

Procedure:
18 ml (0.242 mol) of thionyl chloride are slowly added dropwise to 800 ml of methanol at -10° C., while stirring. A solution of 44.3 g (0.201 mol) of 4-(4-piperidinyl)-butyric acid hydrochloride in 100 ml of methanol is then added dropwise at the same temperature, stirring is continued overnight at room temperature and the mixture is then concentrated to dryness in vacuo. The residue is partitioned between 50% strength potassium carbonate solution and ether. The aqueous phase is extracted twice more with ether. The combined ether extracts are dried and concentrated. The residue is dissolved in methanol and the solution is acidified to pH 6 with ethereal hydrochloric acid and concentrated to dryness in vacuo. The residue which remains is triturated with acetone. The crystals which have separated out are filtered off with suction.
Reaction SMILES: [CH2:1]=[O:2].[N:3]1[C:10]([NH2:11])=[N:9][C:7]([NH2:8])=[N:6][C:4]=1[NH2:5].C=O.[NH2:14][C:15]([NH2:17])=[O:16].N1C(N)=NC(N)=NC=1N.N[C:28](N)=[O:29].C=O.[OH-].[Na+]>>[CH2:28]([NH:14][C:15]([NH2:17])=[O:16])[OH:29].[CH2:1]([NH:5][C:4]1[N:6]=[C:7]([NH2:8])[N:9]=[C:10]([NH2:11])[N:3]=1)[OH:2]
Reactant: NC(N)=O
Reactant: Nc1nc(N)nc(N)n1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCO
Product: Nc1nc(N)nc(NCO)n1

Procedure:
Alternatively, the nitrogen functional groups were introduced from the polymeric resins such as melamine-formaldehyde and urea-formaldehyde. The resins were synthesized by the addition-condensation reactions. Firstly, melamine/urea and formaldehyde were mixed in aqueous media in the molar ratio 1:3/1:2. NaOH was added to this mixture to bring the pH to 11-12 at 60° C., which initiates the addition reaction to form methylolurea/methylolmelamine intermediates. Then the pH was adjusted to around 4-5 using H2SO4 to initiate the condensation/polymerization reaction resulting in the respective resins. The sample was dried using a rotary evaporator at 80° C. under vacuum, and heat-treated in an Ar atmosphere at 800° C. for 1 h.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][N:7]=1
Reactant: BrCC1CC1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 6-bromopyridin-3-ol (10.0 g), (bromomethyl)cyclopropane (7.76 g), potassium carbonate (11.9 g), and DMF (100 mL) was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.0 g) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:30])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]1[C:17]([CH3:29])=[N:18][N:19]2[C:24]3[NH:25][CH2:26][CH2:27][C:23]=3[C:22]([CH3:28])=[N:21][C:20]=12.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34].O>ClCCl>[CH2:31]([S:35]([N:25]1[C:24]2[N:19]3[N:18]=[C:17]([CH3:29])[C:16]([C:9]4[C:8]([CH3:30])=[CH:13][C:12]([CH3:14])=[CH:11][C:10]=4[CH3:15])=[C:20]3[N:21]=[C:22]([CH3:28])[C:23]=2[CH2:27][CH2:26]1)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCS(=O)(=O)Cl
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Reaction time: 2 h
Yield: 27.3 %

Procedure:
Triethylamine (0.091 mL, 0.652 mmol) was added to a solution of 3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (100 mg, 0.326 mmol) prepared in Example 72 in dichloromethane (5 mL). Butanesulfonyl chloride (0.047 mL, 0.358 mmol) was added dropwise at room temperature, followed by stirring for two hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried over MgSO4, and the solvent was evaporated. The residue was subjected to silica gel column cromatography, to give the title compound (38 mg, 27%) as white crystals from a fraction of ethyl acetate-hexane (1:4 v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Cl:18][C:19]1[C:20]([C:29](Cl)=[O:30])=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.O>ClCCl>[Cl:18][C:19]1[C:20]([C:29]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:9])(=[O:10])[NH2:11])[CH:3]=2)=[O:30])=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=C(Cl)c1nc2ccccc2nc1Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Cl)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3-aminobenzenesulfonamide (4.5 g, 26.43 mmol) and pyridine (12.83 mL, 158.6 mmol) in dichloromethane (48 mL) at 0° C. was added 3-chloroquinoxaline-2-carbonyl chloride (6.0 g, 26.43 mmol) in dichloromethane (60 mL) and the mixture was stirred and allowed to warm up to room temperature overnight. To the reaction slurry, water (60 mL) was added. The solid was isolated by filtration, washed with water (3×50 mL), hexane (50 mL) and a small amount of dichloromethane. The solid was dried under vacuum to yield 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (7.1 g, 74%) as a salmon colored solid. ESI-MS m/z calc. 362.02, found 363.3 (M+1)+; Retention time: 1.43 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.40-8.33 (m, 1H), 8.31-8.24 (m, 1H), 8.24-8.14 (m, 1H), 8.12-7.98 (m, 2H), 7.90-7.81 (m, 1H), 7.69-7.58 (m, 2H), 7.47 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9](=[O:34])[NH:10][C:11]1([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:13][CH2:12]1)[CH:6]([CH3:8])[CH3:7].[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>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.O>[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[NH:15][C:14]([C:11]5([NH:10][C:9](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:35])[CH:6]([CH3:8])[CH3:7])[CH2:12][CH2:13]5)=[N:18][CH:17]=4)=[CH:20][CH:21]=3)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)CC1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)CC1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
[2-Methyl-1-(1-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-cyclopropylcarbamoyl)-propyl]-carbamic acid methyl ester (85 mg, 0.21 mmol) and (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (97 mg, 0.21 mmol) in 3:1 DME/H2O (2.5 mL) were treated with Pd(PPh3)4 (10 mg, 0.0084 mmol) and K2CO3 (2 M solution, 0.42 mL, 0.84 mmol). The mixture was stirred in a sealed tube at 80° C. for 3 hours. The mixture was filtered through a fitted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.3 mg, 2%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.93 (s, 2H), 7.84 (m, 4H), 5.20 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 4.01 (m, 2H), 3.83 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H), 3.38 (m, 2H), 2.57 (m, 2H), 2.18 (m, 4H), 2.04 (m, 4H), 1.75 (m, 4H), 1.58 (m, 4H), 0.95 (m, 12H); MS (ESI) m/z 725 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[C:27]([Cl:29])=O>>[ClH:29].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:27]([C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Product: CCC(CC)N1CCC(Cc2noc(-c3ccc4ccccc4c3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 2-naphthoyl chloride.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:59][C:60]1[N:61]([C:70]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[C:73]([CH:80]3[CH2:82][CH2:81]3)=[CH:72][CH:71]=2)[C:62]([S:65][CH2:66][C:67](O)=[O:68])=[N:63][N:64]=1>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:67](=[O:68])[CH2:66][S:65][C:62]3[N:61]([C:70]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[C:73]([CH:80]5[CH2:82][CH2:81]5)=[CH:72][CH:71]=4)[C:60]([Br:59])=[N:64][N:63]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(CCCCN)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)C(CCCCNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-aminohexanoate (N-α-Fmoc-Lysine (NH2)—OMe, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then is purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[CH3:29][C:30]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:21]=[CH:22][C:23]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[N:38][C:30]=3[CH3:29])[CH:3]=2)=[O:6])=[CH:9][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 36.9 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (19 mg, 0.079 mmol) via procedure V to afford 16 mg of N-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-2-(methylsulfonylmethyl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid. MS (Q1) 603 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[OH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 50.8 %

Procedure:
10 g (36 mmol) of 2-bromomethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene, 6 g (36 mmol) of ethyl 4-hydroxybenzoate and 7.2 g (52 mmol) of anhydrous potassium carbonate in 60 ml of dimethylformamide were refluxed for 5.25 h. The mixture was then poured into water and extracted several times with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Recrystallization from methanol resulted in 6.7 g of the title compound of melting point 109°-11° C.
Reaction SMILES: F[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1.C(OCC)(=[O:26])C>O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=[O:26]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CF)cc2-c2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: O=[Mn]=O
Product: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was filtered through Celite and the solution was concentrated to provide the crude aldehyde.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:11]1[C:12]2[C:4]([F:3])=[CH:5][CH:6]=[CH:7][C:8]=2[S:9][CH:10]=1
Reactant: BrBr
Reactant: Fc1cccc2sccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc2scc(Br)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of bromine (9.2 ml) in dichloromethane (200 ml) was added dropwise under nitrogen at −5° C. over 30 minutes to a stirred mixture of 4-fluorobenzo[b]thiophene (24.7 g), sodium acetate (20 g) and dichloromethane (200 ml). The mixture was stirred at ambient temperature for 24 hours, then it was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (50 ml), water (200 ml) and zinc dust (34.3 g) were added, then the mixture was stirred and heated under reflux for 10 hours, cooled to ambient temperature and filtered through Celite. The Celite was washed with ethyl acetate (200 ml) then the combined organic solutions were washed with saturated aqueous sodium chloride solution (100 ml), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by distillation in vacuo to give 3-bromo-4-fluorobenzo[b]thiophene (12.5 g) as a pale yellow oil, b.p. 70-85° C. @ 0.53 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([O:14][CH:15]2[CH2:18][NH:17][CH2:16]2)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N-:21]=[C:22]=[O:23].[Cl:24][C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27](OC1CN(C(NC(C)(C)C)=O)C1)C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([O:14][CH:15]2[CH2:18][N:17]([C:22]([NH:21][CH2:27][C:26]3[CH:47]=[CH:48][C:49]([Cl:51])=[CH:50][C:25]=3[Cl:24])=[O:23])[CH2:16]2)[C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Reactant: [N-]=C=O
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[O:25])[CH2:20]1>>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][CH:15]([N:19]4[CH2:22][CH:21]([NH:23][C:24]([CH2:26][NH:27][C:28](=[O:39])[C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=5)=[O:25])[CH2:20]4)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(c2ccc(N3CCCC3)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(N4CCCC4)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the reductive amination of 4-(4-pyrrolidin-1-yl-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH2:26](I)[CH3:27]>O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[N:10]([CH2:26][CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C1NCN(c2cccc(F)c2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CN(c2cccc(F)c2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 2.4 g of 1-(m-fluorophenyl)-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 40 ml of dimethylformamide was added 0.6 g of 50% sodium hydride and the mixture was stirred for one hour at room temperature. To this was further added 4.6 g of ethyl iodide and the resulting mixture was stirred at 60° C for 1.5 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from ether gave 2.2 g of 1-(m-fluorophenyl)-3-ethyl-4-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as pale yellow prisms, melting at 123° - 124° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(C)cn12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cccc2nc(C)c([N+](=O)[O-])n12
Temperature: 0 °C

Procedure:
To a solution of 1.02 g (5.0 mmol) of 5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine in 2.5 ml of conc. sulfuric acid was added dropwise, while stirring under ice-cooling, 2.0 ml of conc. nitric acid. The mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into ice-water, whose pH was adjusted to 3-with a 10% aqueous solution of NaOH. The resulting crystalline precipitates were collected by filtration, washed with water and dried, followed by further purification by column chromatography (eluent: ethyl acetate) to afford 752 mg of the desired compound (60.4%, a yellow solid).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]C1C=CC(S(O)(=O)=O)=CC=1.O>CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Yield: 1135 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (2.0 g, 9.3 mmol) in methanol (20 mL) was added p-TsOH.H2O (90 mg, 0.50 mmol). The mixture was heated at reflux overnight. Methanol was evaporated and the residue was purified by chromatography on silica gel (3% ethyl acetate in petroleum ether) to afford 4-bromo-2-methyl-benzoic acid methyl ester (1.3 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, J=8.4 Hz, 1H), 7.41-7.36 (m, 2H), 3.89 (s, 3H), 2.57 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([NH:25]C(=O)OCC1C=CC(OC)=CC=1)[CH2:11][CH2:12][C:13](=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]1[CH2:11][CH2:12][C@@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:25]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[NH:25]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)N[C@H](CCC(=O)Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CC[C@@H](Cc2ccc([N+](=O)[O-])cc2)N1
Product: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CC[C@H](Cc2ccc([N+](=O)[O-])cc2)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
To a solution of MOZ protected ketone amine (from Step G, 34 g, 56 mmol) in DCM (350 ml) was added TFA (256 ml) and the resulting mixture stirred at room temperature for 1.5 h. The solution was evaporated under vacuum and residue partitioned between DCM and sat. NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in MeOH (750 ml) and cooled to 0° C. via ice/water bath. Sodium cyanoborohydride (21.2 g, 337 mmol) was then added and the resulting mixture was stirred overnight to allow to warm to room temperature. The mixture was quenched by addition of water and the organics removed under vacuum. The aqueous layer was then extracted with EtOAc (x2) and the combined EtOAc layers washed with sat. NaCl, dried over MgSO4, filtered and evaporated under vacuum. The residue was purified by column chromatography on silica (eluent: gradient rising from 100% Hexanes to 35% EtOAc in Hexanes) to give 16.4 g (63.4%) of the first isomer, (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidine, and 3.1 g (12%) of the second isomer (2R,5R)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-(4-nitrobenzyl)pyrrolidine.