Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:33])[CH2:31][NH2:32])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][NH:32][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:33])[CH3:28]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(NCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 57 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.86 g), glycine ethyl ester hydrochloride (0.65 g) and triethylamine (0.47 g) in dichloromethane (15 ml) yielded the title compound, 0.38 g, m.p. 174.5-176° C. (recrystallized from ethanol:water).
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13].[OH-].[Na+].C(Cl)(Cl)Cl>C1COCC1>[O:8]=[C:1]([NH:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCC(=O)N[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-heptanoyl chloride (440 mL, 2.83 mmol) in THF (250 mL) is added dropwise, over a period of 30 min, to a cold (-5° to 0° C.), vigorously stirred mixture of D-allo-Thr (300 mg, 2.51 mmol) and 2N aq. NaOH (3.5 mL, 7.0 meq) in THF (4.0 mL). The resulting mixture is stirred for 2 h at the same temperature and overnight at room temperature. The volatiles are removed and the residue is diluted with water and acidified, using conc. HCl. The mixture is extracted with EtOAc and the combined organic solution is washed with brine, dried, filtered, and concentrated to provide crude 2c-1 (420 mg, containing 10% excess heptanoyl reagent) which solidifies upon standing. NMR δ1.28 (d, J=6.5, 3 H), 4.20 (m, 1H), 4.61 (dd, J=3.4, 6.6, 1H), 6.56 (br d, J=6.9, 1H); [α]D26 -38±2 (CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[CH:20][N:19]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: NC1CCOCC1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
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: Cc1nnn(-c2ccc(F)cc2)c1COc1cnc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid (83 mg, 0.25 mmol) and TBTU (90 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (216 μL, 1.26 mmol). Then 4-aminotetrahydropyran (28 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (92 mg, 89%) as a white solid. MS: m/e=413.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:15])=[N-]>CO.C(OCC)C>[CH3:15][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:12][CH:11]=1
Reactant: O=C(O)C=Cc1ccc(I)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C=Cc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A stirred, cooled (ice bath) solution of 4-iodo-cinnamic acid in methanol was treated with a solution of diazomethane in diethyl ether. The reaction mixture was allowed to warm to ambient temperature, the volatiles were evaporated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: NCC1CCOCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(CC2CCOCC2)c2nc(Br)cnc2N1
Temperature: 40 °C
Yield: 78.6 %

Procedure:
N-(3,5-Dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (8.0 g, 19.01 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (2.63 g, 22.81 mmol) and diisopropylethylamine (6.64 mL, 38.0 mmol) were placed in a 250 mL round bottom flask, suspended in acetonitrile (80.0 mL) and heated to 40° C. for 16 h. The resulting white precipitate was filtered, washed with acetonitrile followed by hexanes and dried under vacuum to afford the title compound (4.89 g, 14.95 mmol, 79% yield). MS (ESI) m/z 327.4 [M]+, 329.5 [M+2]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH2:65])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:52])[CH3:51].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:50]([O:54][C:55](=[O:66])[C:56]1[CH:64]=[C:63]([NH:65][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH:62]=[C:58]([C:59]([OH:61])=[O:60])[CH:57]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)c1cc(N)cc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)Nc1cc(C(=O)O)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of hexadecandioic acid mono t-butyl ester (100 mg, 0.29 mmol) in dry DCM (2 ml), HOAt (44 mg, 0.29 mmol) and DCC (72 mg, 32 mmol) was added. The mixture was stirred at 50° C. for 1 h. The oil bath was removed. 5-Amino-isophthalic acid mono t-butyl ester (69 mg, 0.29) and DIPEA (0.07 ml, 0.32 mmol) was added. The mixture was stirred at RT over night under nitrogen. The yellow suspension was filtered and the filtrate was concentrated. The residue was redissolved in EtOAc and extracted with 0.1 N HCl (2×), brine (1×), dried (Na2SO4) and concentrated to give a white solid, which was purified twice by flash chromatography using EtOAc/Hept 1:2+5% AcOH. The title compound was obtained in 86% yield (0.140 g) as an oil containing an impurity.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].[CH3:16]O>>[C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@H:6]1[O:7][CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CO
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Yield: 25 %

Procedure:
To a solution of N-acetylglucosamine (50 g, 0.22 mmol) in MeOH (50 ml), a catalytic quantity of Amberlite IR-120 H+ resin is added, and the mixture is heated for 2 days. The mixture is filtered, concentrated and purified by silica gel column chromatography (CH2Cl2/MeOH 5:1), obtaining 10 g of the α-anomer methyl 2-acetamido-2-deoxy-α-D-glucopyranoside (25%) anomer and 40 g of the β-anomer that is isomerised to give the α-anomer methyl 2-acetamido-2-deoxy-α-D-glucopyranoside in the same reaction conditions (70% yield).
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[N:12]=[C:11]([Cl:16])[N:10]=[C:9](Cl)[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].CC(O)C.[OH-].[NH4+:23]>O>[NH2:23][C:9]1[C:8]2[CH2:7][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]([Cl:16])[N:10]=1
Reactant: CCOC(=O)C1CCc2nc(Cl)nc(Cl)c2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1CCc2nc(Cl)nc(N)c2C1
Temperature: 130 °C

Procedure:
A mixture of 6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (7.68 g), 2-propanol (7 mL) and 30% ammonium hydroxide (12 mL) was heated in a sealed tube at 130° C. for 20 min. The tube was cooled and 20 mL of H2O was added to the mixture. The solid which precipitated was collected and dried to yield 4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.[C:21]1([C@H:31]([NH2:33])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:33][C@H:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH3:32])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.512 mmol) of [4-(4-chlorophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 130A, 96.5 mg (0.564 mmol) of (1R)-1-(1-naphthyl)ethylamine, 128 mg (0.67 mmol) of EDC hydrochloride and 83.1 mg (0.62 mmol) of HOBt are dissolved in 2 ml of dry DMF and stirred overnight at room temperature. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1). The target compound is obtained in a yield of 172 mg (75% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1cccnc1N
Reactant: COC(=O)COCCc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2ncccc12
Yield: 54.9 %

Procedure:
A suspension of 2-amino-nicotinamide (250 mg, 1.82 mmol) and [2-(3-fluoro-phenyl)-ethoxy]-acetic acid methyl ester (464 mg, 2.18 mmol) in THF (5 ml) was treated with LiHMDS (1M THF solution, 4.6 ml) overnight at ambient temperature. The yellow suspension was filtrated, the filtrate was brought to dryness and the residue was purified by column chromatography (amino-phase silica gel, CH2Cl2/MeOH, 19/1) to give 2-[2-(3-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one (303 mg, 1 mmol; 55%) as white solid. MS (m/e): 300.2 [M+H]+
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]([CH3:25])=[CH:22][C:23]#[N:24]>C(O)(=O)C>[CH2:1]([S:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:16]([CH3:15])=[C:17]3[C:9]#[N:10])[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)=CC#N
Reactant: O=Cc1ccc2[nH]nc(SCc3ccccc3)c2c1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(SCc4ccccc4)c3c2)C(C#N)=C(C)N1

Procedure:
The crude product obtained in Example 8A and 29.6 mg (0.361 mmol) 3-aminobut-2-enenitrile in acetic acid (4 ml) were heated to 110° C. for 1 h. After cooling, the reaction mixture was directly purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) yielding 30 mg (46% of th.) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:13](=[O:20])[CH2:12][CH2:11]2.[CH:21]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1>ClC(Cl)C>[N+:17]([C:16]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:20])=[CH:9][C:8]=1[NH:7][C:28](=[O:29])[CH2:27][CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:19])=[O:18]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
Pyridine (0.1 g, 1.3 mmol) was added to a suspension of 5-amino-6-nitro-indan-1-one (0.19 g, 1 mmol) in 15 ml of anhydrous dichloroethane followed by the addition of 3-cyclopentylpropionyl chloride (0.193 mg, 1.2 mmol) at room temperature under argon. The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified by column (hexane/EtOAc, 5:1) to give a yellow solid (0.26 g, 83%). 1H-NMR (DMSO-d6): δ 10.47 (s, 1H, NH, exchangeable with D2O), 8.06 (s, 1H), 7.87 (s, 1H), 3.15 (m, 2H), 2.69 (m, 2H), 2.38 (t, 2H, J=7.8 Hz), 1.74 (m, 2H), 1.59-1.46 (m, 7H), 1.08 (m, 2H). MS: 317 (M+1).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][CH2:31][OH:32]>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]
Reactant: COCCO
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: [Na]
Product: COCCOc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OC
Temperature: 125 °C

Procedure:
A mixture of sodium (118 mg, 5.11 mmol) and 2-methoxyethanol (5 mL) is heated at 120-130° C. for 3 hours. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (500 mg, 1.28 mmol) is added and the reaction mixture is heated at 120-125° C. for 1 hour. The temperature of the reaction mixture is increased to 140-150° C. and this temperature is maintained for 2.5 hours. The reaction mixture is cooled to room temperature and diluted with ice cold aqueous sodium bicarbonate. The solid is collected by filtration washing with water and hexane. Purification by flash column chromatography, eluting with 2% methanol in dichloromethane provides 550 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-methoxyethoxy]-3-quinolinecarbonitrile, mp 210-212° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[CH3:26][C:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:41])[N:29]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:28]=1>>[C:12]([C:6]1[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([C:31]3[C:27]([CH3:26])=[N:28][N:29]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:30]=3[CH3:41])=[N:3]2)=[N:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Product: CC(=O)c1cnc2ccc(-c3c(C)nn(C(=O)OC(C)(C)C)c3C)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (92 mg, 0.25 mmol) was reacted with tert-butyl 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (120 mg, 0.37 mmol) to afford crude product (100 mg) as a brown solid which was carried forward without any purification: ESI MS m/z 521 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylate (150 mg, 0.38 mmol) in methanol (50 mL) was added sodium hydroxide (150 mg, 3.75 mmol) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2-(5-fluoro-1-benzofuran-2-yl)-3-(pyrrolidin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (36.5 mg, 25%).
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)(=[O:6])=[O:5])[CH3:3].[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:25][CH2:24][S:26]([CH3:29])(=[O:28])=[O:27])(=[O:6])=[O:5])[CH3:3]
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3CCS(C)(=O)=O)c2c1
Temperature: 100 °C
Yield: 54.4 %

Procedure:
5-(2-Ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole hydrochloride (Preparation 5; 200 mg, 0.56 mmol) was dissolved in N,N-dimethylacetamide (4 ml) under nitrogen at room temperature, then methyl vinyl sulphone (0.06 ml, 0.69 mmol) and triethylamine (0.2 ml) were added. The resulting mixture was heated at 100° C. for 18 hours, allowed to cool, then partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure. The resulting crude material was purified by column chromatography on silica gel, eluting with a gradient of ethanol in dichloromethane (0 to 5% ethanol), to afford the title compound as a gum (130 mg). Rf 0.70 (SS 4). [α]D25 +43° (c=0.1, CH3OH). Found: C,55.38; H,7.12; N,6.50. C20H30N2O4S2 ; 0.10 CH2Cl2 requires C,55.48; H,7.00; N,6.44%. δ(CDCl3): 1.38(3H,t), 1.50-1.90(5H,m), 2.22(1H,m), 2.60-2.80(3H,m), 2.90-3.35(12H,m), 3.48(1H,m), 5.30(0.20H,s,CH2Cl2), 6.98-7.10(2H,m), 7.30(1H,d), 7.44(1H,s), 8.22(1H,br s).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:19]([CH2:20][O:21]C(=O)C)=[C:18]([F:25])[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10])=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[NH2:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:19]([CH2:20][OH:21])=[C:18]([F:25])[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10]
Reactant: CC(=O)OCc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of acetic acid 2-((S)-1-tert-butoxycarbonylaminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-ylmethyl ester (190 mg, 0.44 mmol) in methanol (2 mL) was added HCl in dioxane (4N, 5 mL) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to give the title compound as a beige solid (159 mg, 100%). LCMS (Method C): RT=1.61 min, [M+H]+=372.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=O)=[CH:9][CH:10]=1)=[O:5])[CH3:2].Cl.[NH2:14][OH:15].C(O)C.C([O-])(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:11]=[N:14][OH:15])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)c1ccc(C=O)[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(C=NO)[nH]1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (as prepared in the previous step, 300 mg, 1.80 mmol), hydroxylamine hydrochloride (560 mg, 8.10 mmol), ethanol (10 mL), sodium acetate (1.10 g, 13.4 mmol) and water (10 mL) was stirred at 90° C. for 30 min. The solvents were removed in vacuo and the solid was collected on a Buchner funnel and washed with water (10 mL) to yield 226 mg (69%) of the title compound as a white solid: LC-MS (ESI, m/z): Calcd. for C8H11N2O3, 183.1 (M+H); found: 183.0.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.O1CCOCC1>O>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Solvent: C1COCCO1
Solvent: O
Product: C1CN2CCC(CC2)N1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To the solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAlH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 h and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]([CH3:18])C(O)=O)=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[O:20]1CCC[CH2:21]1>>[Cl:1][C:2]1[C:3]([CH2:14][CH2:18][CH2:21][OH:20])=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C(=O)O)c1c(Cl)cccc1-c1ccccc1
Solvent: O
Product: OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a dry argon atmosphere, borane-tetrahydrofuran complex (230 ml of a 1.5 M solution in tetrahydrofuran) was added dropwise to a stirred solution of (3-chloro[1,1'-biphenyl]-2-ylpropanoic acid (40.0 g, 0.15 mole) in tetrahydrofuran (250 ml). The reaction mixture was stirred at room temperature for approximately 18 hours. Water (30 ml) was then added to the reaction mixture during a 0.5 hour period. The solvent was removed from the mixture under reduced pressure to yield an oil. The oil was partitioned betwen methylene chloride and dilute aqueous sodium hydroxide. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield 3-(3-chloro[1,1'-biphenyl]-2-yl)-1-propanol as an oil.