Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12]1)#[N:29]
Reactant: N#CCBr
Reactant: NS(=O)(=O)c1ccc(N[C@@H]2CCNC2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
To a solution of EXAMPLE 428C (440 mg) in anhydrous N,N-dimethylformamide (10 mL) was added sodium carbonate (132 mg). To the resulting suspension was added 2-bromoacetonitrile (0.077 mL) and the mixture was heated at 60° C. for 18 hours. The crude material was isolated by concentration and was purified on silica gel, and was eluted with a 0.5, 2.5, and 5% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[F:14])[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[F:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:7][CH:6]=[C:5]([C:3]3[N:15]=[C:16]([NH2:18])[S:17][CH:2]=3)[C:13]=12
Reactant: NC(N)=S
Reactant: O=C(CBr)c1c[nH]c2nccc(F)c12
Solvent: CCO
Product: Nc1nc(-c2c[nH]c3nccc(F)c23)cs1
Temperature: 70 °C
Yield: 65.7 %

Procedure:
To an ethanol suspension of 2-bromo-1-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (3.00 g 0.0117 mol) was added thiourea (1.18 g, 0.0234 mol), the reaction mixture was heated at 70° C. for 1 h. The suspension was filtered while still warm and to the filtration cake was added sat. sodium carbonate solution until the aqueous phase pH was around 7.5. The suspension was filtered to afford 1.8 g free base (75%). H NMR, DMSO-d6: 6.78 (s, 1H), 6.9 (s, br, 2H), 6.98 (m, 1H), 7.71 (s, 1H), 8.25 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]([O:19]C)=O)[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:21]>CO>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH:10]([C:17]([NH2:21])=[O:19])[C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCCc2ccc(-c3ccccc3)nc21
Temperature: 100 °C

Procedure:
Methyl 2-phenyl-5,6,7,8-tetrahydroquinoline-8 -carboxylate (4 g.) was dissolved in methanol previously saturated with ammonia (90 ml.) and heated in a bomb at 100° C. for 4 days. Removal of the solvent in vacuo gave an oily solid which on recrystallisation from ethyl acetate gave the title compound as colourless needles (1.5 g.) mp 145° C. Found: C, 76.4; H, 6.5; N, 11.1% C16H16N2O requires: C, 76.2; H, 6.4; N, 11.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:14]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:14]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc(CO)cc2Cl)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(Cl)cc(C=O)cc2Cl)cc1OC1CCCC1
Yield: 54.8 %

Procedure:
A solution of N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (4.4 g) in dichloromethane (30 mL) is treated with activated manganese dioxide (6.2 g), and the mixture is stirred at reflux for 24 hours. The mixture is filtered, the filtrate is evaporated, and the resulting residue is subjected to flash chromatography on silica gel, eluting with ethyl acetate, to give N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (2.4 g), m.p. 96-98° C. [Elemental analysis: C,59.0; H,5.1; N,3.1%; calculated: C,58.8; H,4.7; N,3.4%].
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH2:16])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[NH:15][NH:16][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(NN)nc2ccccc2c1=O
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCn1c(NNC(=O)CCCl)nc2ccccc2c1=O
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a stirred mixture of 4.50 g of 3-allyl-2-hydrazino-quinazolin-4(3H)-one (0.0208 mol) and 5.75 g of anhydrous potassium carbonate (0.0416 mol; 2 eq) in 100 ml of chloroform at room temperature as added 2.2 ml of 3-chloropropionyl chloride (2.91 g; 0.023 mol; 1.1 eq). Almost immediately, a precipitate appeared and after 1 hr, 50 ml of water were added to the stirred mixture to dissolve any potassium carbonate. The mixture was filtered and the product was washed twice with water then twice with ether, crystallized from ethanol and dried under vacuum over P2O5 at 80° C. to obtain 5.79 g (91% yield) of 3-allyl-2-(2-(3-chloropropionyl)hydrazino)quinazolin-4(3H)-one melting at 151°-153° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]([NH2:29])(=[O:28])[CH3:27]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][C:26](=[O:28])[CH3:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(N)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: CC(=O)Nc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and acetamide. MS obsd. (ESI+) [(M+H)+] 396, 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.10-8.06 (m, 2 H), 7.97-7.85 (d, J=8.4 Hz, 1 H), 7.82-7.80 (d, J=9.2 Hz, 1 H), 7.76-7.72 (m, 2 H), 7.58-7.54 (m, 2 H), 5.28 (s, 2 H), 4.60 (s, 2 H), 3.77-3.71 (m, 2 H), 2.52 (s, 3 H), 2.40 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CO.[Cl-].[Na+].O.CC(O)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(-c2ccc(Cl)nc2)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
A solution of 3-[5-(6-Chloro-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep93, 0.82 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 186 mg, 0.82 mmol), and AcOH (58 μl) in dichloroethane-MeOH (10-0.1, 8 ml) was cooled to 0° C. NaBH(AcO)3 (182 mg, 0.86 mmol) was added portionwise. The mixture was stirred at 0° C. for further one hour and then basified with 1N NaOH. Brine was added and the product extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in the presence of PS-isocyanate. The mixture was filtered and the solvent evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 140 mg of the title compound (34% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: Cc1cccc(C#CC=C2CCN(c3ccccc3)CC2)n1
Temperature: 110 °C
Yield: 100 %

Procedure:
A mixture of the compound of Example 3 (0.22 g, 1.04 mmol), bromobenzene (0.17 g, 1.04 mmol), cesium carbonate (0.68 g, 2.1 mmol), BINAP (0.031 g, 0.05 mmol), palladium(II)acetate (0.01 mg, 0.05 mmol), in anhydrous and degassed toluene (10 mL) was heated at 110° C. under a nitrogen atmosphere for 12 h in a sealed vessel. The reaction mixture was cooled, poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography (EtOAc—Petroleum Ether 2:8) affording the title product (0.30 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8]1[N:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:10]2[C:15]([C:16]=1[CH:17]=O)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:8]1=2
Reactant: COCCOCn1c(Cl)c(C=O)c2ccccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCn1c2ccccc2c2cc(C(=O)OC)sc21
Reaction time: 8 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1 g of (78) and 1.1 g of K2CO3 in 10 ml of MeOH. The reaction was stirred overnight, and then 20 ml of water was added. The mixture was extracted with EtOAc, and the organic layer washed with water, dried and evaporated to give (79) as a yellow oil. Yield 880 mg. 1H-NMR (ppm): 8.1(s, 1H); 7.8(d, 1H); 7.5(d, 1H); 7.3(m, 2H); 5.6(s, 2H); 3.9(s, 3H); 3.5(m, 4H); 3.35(s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:14])C.OO>O1CCCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: OB(O)c1cccc(Br)c1F
Agent: OO
Solvent: C1CCOC1
Product: Oc1cccc(Br)c1F
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3-bromo-2-fluoro-phenylboronic acid (25.0 g, 0.114 mol) in tetrahydrofuran (250 mL) was added glacial acetic acid (150 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 25 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 24 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-bromo-2-fluoro-phenol (19.50 g, 89%) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCn1c(CCOC)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine (1.50 g, 5.01 mmol) was reacted with butyl isocyanate to provide 1.13 g of N- (3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl)-N′-butylurea as an off-white powder, m.p. 159-160° C. Analysis: Calculated for C21H30N6O2. 0.29H2O: %C, 62.47; %H, 7.63; %N, 20.82; Found: %C, 62.64; %H %N, 21.17.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C@@H:10]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[C:18]([NH2:26])[C:17]=4[N:27]=[C:14]3[CH2:13][O:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](CCl)COC1
Product: CN1CCN(C[C@H]2COCc3nc4c(N)nc5ccccc5c4n32)CC1
Temperature: 150 °C
Yield: 16.5 %

Procedure:
Methyl piperazine (0.3 mL, 2.5 mmol) was added to a vial containing (11R)-11-(chloromethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (90 mg, 0.31 mmol). The vial was placed in a stainless-steel, high-pressure vessel and heated to 150° C. for 18 hours. The reaction mixture was cooled to ambient temperature. The resulting light brown oil was purified by chromatography (SiO2, 0-30% CMA/CHCl3). The resulting oil was slurried in acetonitrile to produce a solid which was isolated by filtration to give 18 mg of the desired product as a tan solid, mp 187-190° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14](OC1C(Cl)=CC(Cl)=CC=1Cl)(=[O:28])[CH2:15][C:16](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:17].ClC1C=CC=CC=1>CCCCCC>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([OH:28])=[CH:15][C:16](=[O:17])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCSc1nnc(N)s1
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: CCCCCCSc1nn2c(=O)cc(O)nc2s1
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 65.2 g of the thus obtained 2-amino-5-hexylthio-1,3,4-thiadiazole, 141.7 g of bis(2,4,6-trichlorophenyl) malonate and 240 ml of chlorobenzene was heated to 137°~140° C. and stirred for 1 hour. After cooling, hexane was added to the mixture, and the formed precipitate was separated by filtration, the residue was washed with hexane, and thus 74.7 g of 2-hexylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one was obtained. m.p. 187°~192° C. Yield 87%.
Reaction SMILES: C(O[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:28])[CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:14]2=3)=[CH:7][CH:6]=1)C.[OH-].[NH4+:31]>O>[CH3:27][N:24]1[CH2:25][CH2:26][C:14]2[N:13]([CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([NH2:31])=[O:29])=[CH:10][CH:9]=3)[OH:28])[C:21]3[CH:20]=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CCOC(=O)c1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(C(N)=O)cc2)CCN(C)C1
Temperature: 25 °C

Procedure:
A solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzoicacid ethyl ester (90 mg, 0.229 mmol) in 25% ammonium hydroxide solution (5 mL) was stirred at 120° C. for 1 h. The progress of reaction was monitored by NMR and LCMS. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-ethyl]-benzamide (3 mg) which was separated by chiral preparative HPLC to obtain 139a and 139b. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.18 (t, 2H), 7.4 (d, 1H), 7.31 (d, 2H), 7.23 (s, 1H), 7.03 (t, 1H), 5.08 (t, 1H), 4.64 (dd, 1H), 4.33 (m, 2H), 4.21 (dd, 1H), 3.71 (t, 1H), 3.45 (bs, 1H), 3.12 (m, 1H), 3.09 (d, 3H), 2.6 (d, 1H), 2.41 (s, 3H).
Reaction SMILES: N12CCN(CC1)CC2.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)(=[O:19])[C:17]#[CH:18].[OH-].[Na+]>C1COCC1>[C:9]1([S:15][CH:18]=[CH:17][C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Reactant: Sc1ccccc1
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
To a stirred solution of 1,4-diazabicyclo[2.2.2]octane (DABCO, 10 mg, 0.89 mmol) and thiophenol (99 mg, 0.89 mmol) in dry THF (20 mL) at RT was added compound 1 (200 mg, 0.89) dissolved in dry THF (2 mL) through a syringe over 12 min. The reaction mixture was further stirred for 20 min. 10% NaOH(aq) was added. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and the solvent was removed by evaporation. The crude product was purified by column chromatography using ethyl acetate:hexane (2:8) as an eluent to give compound 4 (254 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 5.84 (d, J=15.0 Hz, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.46 (m, 6H), 7.58 (m, 6H), 8.05 (d, J=15.0 Hz, 1H). HRMS ESI (m/z): Calculated for C21H16O2S ([M+H]+): 333.0871. found: 333.0852.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:32])[CH:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][C:16]([NH2:31])=[C:17]([O:19][CH:20]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=3[Cl:30])[CH3:21])[CH:18]=2)[CH:10]=[N:9]1)[CH3:7].C1COCC1.CO>O>[NH2:31][C:16]1[N:15]=[CH:14][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH:6]([CH3:7])[C:5]([OH:32])=[O:4])[CH:12]=2)=[CH:18][C:17]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21]
Reactant: COC(=O)C(C)n1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(Oc1cc(-c2cnn(C(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 104.7 %

Procedure:
A solution of LiOH (34 mg, 1.4 mmol) in water (0.4 mL) was added to a solution of 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid methyl ester (70 mg, 0.15 mmol) in a mixture THF (1.5 mL) and MeOH (0.4 mL). After stirring overnight, the reaction was partitioned between dichloromethane and half-saturated brine. A small amount of ethanol was added and the pH was adjusted to 7 with 1 M HCl. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and concentrated by rotary evaporation to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid (69 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](O)(=[O:10])=[O:9])[CH:7]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([Cl:17])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)O)c1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1

Procedure:
In a similar fashion using route 39 general procedure 96, 5-methyl-2-nitro-benzenesulfonic acid 449 (1.8 g, 8.2 mmol), SOCl2 (10 ml) and DMF (0.18 ml) at 90° C. for 3 h gave the title compound (1.2 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C)C=O>[C:12]1([NH:11][C:5]2([CH2:4][NH:3][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CBr
Reactant: NCC1(Nc2ccccc2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCC1(Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
110 mg (2.69 mmol) of sodium hydride are added to a solution of 500 mg (2.45 mmol) of (1-aminomethylcyclohexyl)phenylamine in 20 ml of dimethyl formamide. The solution is stirred for 1 h at room temperature and 270 μl (2.45 mmol) of ethyl bromoacetate are added. The reaction medium is stirred at room temperature for 2 h. It is then poured into water and extracted with ethyl acetate. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated. The residue is chromatographed on silica gel (heptane then heptane/ethyl acetate 90/10, v/v). 530 mg of ethyl [(1-phenylamino-cyclohexylmethyl)amino]acetate are obtained in the form of a colorless oil. Yield=75%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:17]3=[C:18]([CH2:20][CH2:21][N:16]3[CH2:15][C@@H:14]3[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][C@H:13]23)[CH:19]=1>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17]3=[C:18]([CH2:20][CH2:21][N:16]3[CH2:15][C@@H:14]3[CH2:22][NH:23][CH2:24][C@H:13]23)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCc4cc(N)cc(c43)[C@H]2C1
Product: c1ccc(CNc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CC3)cc1

Procedure:
Using benzaldehyde and following the procedures described in EXAMPLE 76, (±)-cis tert-butyl 2-amino-4,5,7a,8,10,10a-hexahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline-9(7H)-carboxylate was converted into (±)-cis-N-benzyl-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinolin-2-amine, bis-trifluoroacetic acid salt, after HPLC purification (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). This material was free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to the title compound of EXAMPLE 118 as the free base. LRMS (ES)+: 306.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1Cl
Yield: 43 %

Procedure:
The title compound is prepared from 3-amino-4-chloro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 43% of theory; LC (method 4): tR=1.97 min; Mass spectrum (ESI+): m/z=327/329 (Cl) [M+H]+.